An Update on Poly(ADP-ribose)polymerase-1 - ACS Publications

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An Update on Poly(ADP-ribose)polymerase‑1 (PARP-1) Inhibitors: Opportunities and Challenges in Cancer Therapy Ying-Qing Wang,†,∥ Ping-Yuan Wang,‡,§,∥ Yu-Ting Wang,† Guang-Fu Yang,§ Ao Zhang,*,‡ and Ze-Hong Miao*,† †

Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China ‡ CAS Key Laboratory of Receptor Research, and Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Lu, Building 3, Room 426, Pudong, Shanghai 201203, China § Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, China S Supporting Information *

ABSTRACT: Poly(ADP-ribose)polymerase-1 (PARP-1) is a critical DNA repair enzyme in the base excision repair pathway. Inhibitors of this enzyme comprise a new type of anticancer drug that selectively kills cancer cells by targeting homologous recombination repair defects. Since 2010, important advances have been achieved in PARP-1 inhibitors. Specifically, the approval of olaparib in 2014 for the treatment of ovarian cancer with BRCA mutations validated PARP-1 as an anticancer target and established its clinical importance in cancer therapy. Here, we provide an update on PARP-1 inhibitors, focusing on breakthroughs in their clinical applications and investigations into relevant mechanisms of action, biomarkers, and drug resistance. We also provide an update on the design strategies and the structural types of PARP-1 inhibitors. Opportunities and challenges in PARP-1 inhibitors for cancer therapy will be discussed based on the above advances.

1. INTRODUCTION Poly(ADP-ribose)polymerases (PARPs) are a family of enzymes that catalyze the transfer of ADP-ribose from nicotinamide adenine dinucleotide (NAD+) onto acceptor proteins. Among this family, which consists of at least 17 members, PARP-1 is the most widely investigated. It functions primarily as a DNA repair factor, especially in base excision repair (BER).1−6 In 2010, Ferraris and colleagues systematically reviewed the catalytic function of PARP-1, the rationale for targeting PARP-1 as a therapeutic approach, the pharmacophore of its inhibitors, and the progress in related drug discovery.1 Since then, important advances and breakthroughs have been achieved in the field of PARP-1 inhibitors, including (a) the failure of iniparib7 (1, BSI-201, Figure 1) in its clinical trials and the successful approval of olaparib8 (2, also known as AZD2281 and LYNPARZA; Figure 1), (b) the clinical development of several new inhibitors, (c) the emergence of new anticancer mechanisms, (d) the identification of new biomarkers, (e) the exploration of drug resistance mechanisms, © 2016 American Chemical Society

and (f) the establishment of new design strategies and structural types of PARP inhibitors, such as those with high selectivity. All these advances are dramatically reshaping R&D and clinical applications in the context of PARP-1 inhibitors. Therefore, now is the time to combine all the latest developments to provide a solid foundation for studies of PARP-targeted cancer therapy and to propose future directions. The clinical development of PARP-1 inhibitors was not smooth but was ultimately successful. Compound 1 was the first PARP-1 inhibitor tested in phase III clinical trials for triplenegative breast cancer (TNBC) (Figure 1).7 Unfortunately, the expanded phase III clinical trial of this compound was announced to be unsuccessful in 2011.9 Phase II trials for nonsmall cell lung cancer (NSCLC) also showed no improved objective response.10 The subsequent investigations for the causes of these failures proved that 1 was not a true PARP-1 Received: January 13, 2016 Published: July 14, 2016 9575

DOI: 10.1021/acs.jmedchem.6b00055 J. Med. Chem. 2016, 59, 9575−9598

Journal of Medicinal Chemistry

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Figure 1. Chemical structures of some PARP-1 inhibitors that are currently being or have been (gray structures) evaluated clinically for cancer therapy.

treat patients with metastatic castration-resistant prostate cancer carrying BRCA1/2 or ataxia telangiectasia mutated (ATM) mutations.19

inhibitor due to its poor PARP-1 inhibition (IC50: approximately 100 μM)11 and its inability to selectively kill homologous recombination repair (HRR)-deficient cells.12 Later in the same year, AstraZeneca announced that it would discontinue its planned phase III clinical trials of the PARP-1 inhibitor 2 because of its poor effectiveness in a phase II study on ovarian cancer.13 However, a positive result was obtained from a subsequent retrospective analysis of the data from this phase II clinical trial. When patients were reassigned by BRCA status, the median progression-free survival (PFS) of the patients with BRCA mutations was significantly longer in the 2 treatment group than in the placebo group (11.2 months vs 4.3 months); however, the difference between the groups of wildtype BRCA patients was lower (7.4 months vs 5.5 months).14 This result demonstrated both that patients with BRCA mutations might benefit from treatment with 2 and indicated that the monotherapy of 2 was an effective targeted therapy for platinum-sensitive recurrent ovarian cancer with BRCA mutations. This result led to a restarting of the phase III clinical trials of 2 in 2013. Together with some additional results,15,16 this study led directly to the approval of 2 for the treatment of advanced ovarian cancer in patients with BRCA mutations by the European Union17 and by the U.S. Food and Drug Administration (FDA)18 in December 2014. The approval of 2 marked the successful establishment of PARP-1 inhibition as a clinically efficacious therapeutic strategy for cancer and thus reactivated the field of PARP-1 inhibition for cancer therapy. Moreover, in January 2016, the FDA further granted the Breakthrough Therapy designation (BTD) for 2 to

2. PARP-1 INHIBITORS IN CLINICAL EVALUATION FOR CANCER THERAPY To our knowledge, 13 PARP-1 inhibitors are currently being or have been tested in the clinic for cancer therapy. Among them, three (1, 9,20,23 and 1021,24) were discontinued and nine are active in various clinical trials including 2, rucaparib (3),25 niraparib (4),26 veliparib (5),27 talazoparib (6),28 E7449 (7),29 E7016 (8),30 BGB-290 (12,31 chemical structure not disclosed), and ABT-767 (13,32 chemical structure not disclosed) (Figure 1). The current clinical status of one inhibitor (11,22 AZD2461) is unknown (Table 1). Almost all of these inhibitors except 1 (not a true PARP-1 inhibitor, as described above) show potent but nonselective inhibition on PARP-1 and PARP2 enzymatic activity, with IC50s in the nM range; however, some IC50 values are not available. Their chemical structures (Figure 1) contain an amide pharmacophore that mimics NAD+, one of critical substrates of PARPs, suggesting that these inhibitors could inhibit PARP-1 in a competitive manner with NAD+. Although one phase I clinical trial of 11 has been completed (NCT01247168), no results or any information about its further clinical development are available. Compounds 1, 9, and 10 were eliminated for clinical evaluation due to poor therapeutic effectiveness9 (1, phase III), poor pharmacokinetic features, or severe toxicity (9, phase I/II;23 10, phase Ib24). Among the nine PARP-1 inhibitors currently in active clinical 9576



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Table 1. PARP-1 Inhibitors That Have Been (Gray) or Are Being Clinically Evaluated for Cancer Therapya

a

The listed clinical trials are for the highest stage of corresponding inhibitors. Gray represents the PARP-1 inhibitors that currently have unknown or terminated clinical trial status. NA*: The IC50 values for PARP-1 and/or PARP-2 are not available. Compound 8 was reported to inhibit PARP activity by 84% at 3 μM.59

Table 2. Therapeutic Responses of Different Cancers to 2 as Monotherapy (400 mg BID) in Phase II Clinical Studiesa tumor types ovarian cancer

breast cancer

pancreatic cancer prostate cancer Ewing sarcoma

NCT no.

patients with BRCA mutations

CR (%)

PR (%)

SD (%)

ORR (%)

PFS (months)

CBR

DOR (months)

median OS (months)

refs

00494442 00679783 00628251 00753545 01078662 00679783 01078662 00494234 01078662

33 17 32 74 193 8 62 27 23

6 0 − − 3 0 0 4 4

27 41 − − 28 0 13 37 17

36 29 59 − 40 63 47 44 35

33 41 31 − 31 0 13 41 21

5.8 7.4 8.8 11.2 7.0 3.6 3.7 5.7 4.6

52 76 − − − 63 − − −

9.7 − 6.8 − − − − 4.8 −

− − − − 16.6 − 11.0 − 9.8

38 15 39 13,14 16 15 16 40 16

01078662 01682772 01583543

8 16 (DNA-repair defects) 12 (no BRCA test)

0 − 0

50 − 0

25 − 33

50 88 −

7.2 9.8 1.4

− − −

− − −

18.4 13.8 −

16 41 42

b

a

Abbreviations: CBR, clinical benefit rate; CR, complete response; DOR, duration of response; PR, partial response; SD, stable disease. bNA, no data available.

trials, five are undergoing phase III trials, including 2−6, while the other four are still in early phase clinical trials, i.e., 729 in phase Ib/I, 830 in phase II, 1231 in phase Ib, and 1332 in phase I (Table 1). Most of these clinical trials are designed to primarily test the compounds as monotherapies against breast, ovarian, or pancreatic cancers harboring BRCA defects. In addition, or in conjunction with these efforts, the effects of these

compounds in combination with several conventional chemotherapeutic drugs are also being determined against other solid tumors, including NSCLC and glioblastoma (Table 1). Currently, no reports about these ongoing clinical trials are available. Among all the PARP-1 inhibitors mentioned above, 2 has been clinically evaluated most extensively and its results can be 9577



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with cisplatin plus gemcitabine, the alkylating agent dacarbazine, or the topoisomerase I (Top1) inhibitor topotecan could not be tolerated due to increased toxicities46,47 or showed no significant clinical advantage over the single-agent therapy.48 In contrast, both phase I and II trials indicated that 2 was synergistic with paclitaxel or paclitaxel plus carboplatin in TNBC, ovarian, and gastric cancers.49−52 In particular, the combination of 2 and paclitaxel caused a high objective response rate (ORR) of 34.6% in a subpopulation of gastric cancer patients with low expression of ATM (ATMlow).52 This result encouraged further investigation of this combination in phase III trials for gastric cancer (Table 1). In addition, 2 in combination with protein kinase inhibitors also showed promising results. Compound 2 in combination with the angiogenesis inhibitor bevacizumab was well tolerated in a phase I study.53 Both phase I and II clinical trials revealed that the combination of 2 and the vascular endothelial growth factor receptor (VEGFR) inhibitor cediranib improved the therapeutic efficacy in patients with ovarian cancers regardless of BRCA status (Supporting Information, Table 1).54,55 The panphosphatidylinositol 3-kinase (PI3K) inhibitor 5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (BKM120) and the epidermal growth factor receptor (EGFR) inhibitor gefitinib were also found to offer additional clinical benefit with the use of 2.56,57 All these clinical explorations help to expand the clinical uses of 2 itself, and the results are also valuable for the clinical development of other PARP-1 inhibitors.

considered to represent the recent advances in the clinical development of PARP-1 inhibitors either as a single agent or as part of a combination therapy. Therefore, we here discuss the clinical trials of 2 in hopes of further understanding the status of the clinical development of PARP-1 inhibitors. Five phase I clinical trials of 2 monotherapy have been reported,33−37 of which one compared the bioavailability of its two different oral formulations (capsule and tablet).35 The results with the capsule formulation revealed a maximum tolerated dose (MTD) of 400 mg BID.33,34 To reach this dose, 16 capsules (50 mg/capsule) each day were required which might compromise patient compliance. Therefore, the tablet formulation was developed and showed at least 2-fold improvement in bioavailability.35 The tablet formulation was used in later studies, especially in phase III clinical trials. Compound 2 is absorbed rapidly and reaches its peak plasma concentrations 1−3 h after single dosing. It has a terminal halflife (t1/2) of approximately 10 h, an average apparent distribution volume (Vd) of 40.3 L, and an average plasma clearance rate (CL) of 4.6 L/h/kg. Its PARP-1 inhibition can be monitored by the formation of phosphorylated histone H2AX (γH2AX) foci in plucked eyebrow-hair follicles and poly(ADPribose) (PAR) reduction in tumor tissues and peripheral blood mononuclear cells (PBMCs).33 The primary toxicities of 2 are related to gastrointestinal reactions and myelosuppression. Very favorably, 2 did not show interethnic differences in its safety, tolerability, and pharmacokinetic/pharmacodynamic (PK/PD) profiles.33−36 In addition, phase I studies revealed preliminary therapeutic activity as a monotherapy in cancers harboring BRCA1 or BRCA2 mutations.33,34,37 Compound 2 was subsequently tested in the phase II clinical trials. There are eight phase II monotherapy studies that have been reported for ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, or Ewing sarcoma (Table 2).13−16,38−42 In patients with Ewing sarcoma, no significant responses or durable disease control was observed.34 All other tested cancers showed different degrees of therapeutic responses, and BRCAmutated ovarian cancer showed the best responses. Compound 2 was tested in a proof-of-concept and a nonrandomized phase II trial, respectively,15,38 and both studies indicated that 2 was promising in BRCA-mutated ovarian cancer. Two randomized phase II studies further strengthened the evidence of the effectiveness of 2 to treat platinum-sensitive relapsed high-grade serous ovarian cancer (HGS-OvCa).13,14,39 Unexpectedly, however, patients with breast cancer, even those carrying BRCA mutations, showed much weaker responses to 2 (Table 2). Pancreatic and prostate cancers with BRCA mutations were also found to improve from 2 monotherapy.16 Moreover, in a recent phase II study in patients with prostate cancer, four of five patients with ATM aberrations showed responses to 2.41 Together with other supporting evidence, this result led to the FDA classification of 2 as a BTD for prostate cancer.19 There have been 15 clinical trials reported for combinational uses of 2 (Supporting Information, Table 1), including 12 phase I trials and three phase II trials. The anticancer drugs that are used in combination with 2 primarily include DNAdamaged agents, microtubule inhibitors, angiogenesis inhibitors, and kinase inhibitors. The results from six phase I studies on DNA-damaging agents revealed that 2 improved the therapeutic responses of patients with different cancers to carboplatin, cisplatin, and the topoisomerase II inhibitor pegylated liposomal doxorubicin (PLD), although the toxicities of these drugs were also increased.43−45 The combination of 2

3. ANTICANCER MECHANISMS OF PARP-1 INHIBITORS The anticancer mechanism of PARP-1 inhibitors as monotherapy has not been fully understood yet. Initially, PARP-1 inhibitors were believed to inhibit the enzymatic activity of PARP-1 and to impair BER-mediated DNA single-strand break (SSB) repair. Due to replication fork collision, the accumulated SSBs are converted to DNA double-strand breaks (DSBs), which are primarily repaired via the HRR pathway to allow cell survival. Therefore, in HRR-deficient cancers, including BRCA1- or BRCA2- deficient cancers, PARP-1 inhibition results in cell death via a synthetic lethality mechanism and elicits anticancer effects.1,3 However, this mechanism can not fully explain why the capacity of the inhibitors to inhibit PARP1 catalytic activity is poorly correlated with their cell killing in HRR-deficient cells. Moreover, PARP-1 inhibitors delay SSB repair and induce cytotoxicity to a greater extent than PARP-1 depletion. Additionally, PARP-1 itself is essential to the cytotoxic effects of PARP-1 inhibitors.60 Therefore, some new mechanisms of action by which PARP-1 inhibitors elicit cell killing and anticancer effects have been proposed. The current evidence shows that there are three possible mechanisms for the effects of these inhibitors, as follows. 3.1. Interactions between DNA, PARP-1 and its inhibitors. Interactions between DNA, PARP-1, and its inhibitors lead to the inhibition of PARP-1 catalytic activity and trapping of the DNA−PARP-1 complexes. These mechanisms are likely to be the most basic anticancer mechanisms of PARP-1 inhibitors, although there are related events that remain to be clarified.61 The mechanism related to the inhibition of PARP-1 catalytic activity was mentioned above. Therefore, here we focus on the trapping of DNA− PARP-1 complexes. 9578



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Figure 2. Simplified schematic representation of the repair pathways for SSBs and DSBs and the forms of synthetic lethality caused by PARP-1 inhibitors. The cyan rectangles represent different repair pathways. In the text, red represents the target (PARP-1) or the most important HRR defects (BRCA1/2); blue, green, orange, and purple represent the potential biomarkers, i.e., HRR factors and their downstream-regulated factors, factors that regulate HRR factors, the target PARP-1 and its related factors, and other molecules, respectively.

Detectable SSBs were not found to increase in BRCA2deficient cells treated with PARP-1 inhibitors.5,61,66 Therefore, further investigations into the DNA−PARP trapping are still needed, especially with respect to the relationship of this effect with the cytotoxicity of PARP-1 inhibitors and their therapeutic implications. 3.2. Synthetic Lethality. Synthetic lethality is likely to be the direct mechanism of cell killing by PARP-1 inhibitor monotherapy. There are three known forms of synthetic lethality (Figure 2). In addition to classical synthetic lethality between BER inhibition by PARP-1 inhibitors and HRR defects (e.g., BRCA1/2 loss-of function mutations), synthetic lethality was recently shown to occur between Alt-NHEJ inhibition (via PARP-1 inhibition) and HRR defects.67 Alt-NHEJ, also known as microhomology-mediated end-joining (MMEJ), is an errorprone DSB repair mode requiring PARP-1 and DNA polymerase θ (Pol θ, also known as Pol Q in mice) (Figure 2).67,68 PARP-1 stimulates HRR by PARylating BRCA1associated RING domain protein 1 (BARD1) to promote the recruitment of BRCA1 to damage sites. In HRR-proficient cells, DSBs are repaired predominantly by HRR. In contrast, HRRdeficient cancers are dependent on Alt-NHEJ,67,68 and AltNHEJ inhibition by PARP-1 inhibitors induces cancer cell killing in this context. A third form of synthetic lethality may occur between NHEJ activation by PARP-1 inhibitors and HRR defects. PARP-1 suppresses the error-prone NHEJ repair pathway by PARylating Ku70/Ku80 and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). PARP-1 inhibitors might remove this suppression and enhance NHEJ activity. In HRR-deficient cells, active NHEJ causes increased chromosomal rearrangements and mutations, leading to cell death.61 At present, however, it is unclear to what degree these three forms of synthetic lethality contribute to the anticancer activity of PARP-1 inhibitors. 3.3. Possible Anticancer Mechanisms of PARP-1 Inhibitors That Are Unrelated to DNA Repair. Although most studies on the anticancer mechanisms of PARP-1

Noncovalent DNA−PARP complexes exist normally in intact cells. PARP-1 inhibitors bind to the NAD+-binding pocket of PARP-1 (and/or PARP-2), induce anallosteric conformational change in PARP-1 (and/or PARP-2), and stabilize the reversible association of PARP-1/2 with DNA. This process is referred to as the trapping of DNA−PARP-1/2 complexes.60,62−64 DNA−PARP trapping leads to persistent DNA− PARP complexes at SSBs, and during S phase, trapped DNA can undergo lethal DSBs in HRR-deficient cells, causing cell death. This effect has been proposed as a mechanism by which PARP-1 inhibitors exert anticancer activity.60,62 Systematic comparisons62−64 reveal that the DNA−PARP trapping capacity of PARP-1 inhibitors has a much higher correlation with their cytotoxicity than their ability to inhibit PARP-1 catalytic activity. However, a recent study with 2, 4, 5, and 6 indicates that DNA−PARP trapping by PARP-1 inhibitors is not an allosteric effect but is correlated with catalytic inhibition linearly in biochemical systems and nonlinearly in cells. The levels of DSBs (as reflected by γH2AX) are more significantly correlated with cell death than are levels of trapping. Moreover, PARP inhibitors with different trapping capacity can elicit comparable in vivo efficacy at MTDs.65 In many ways, PARP-1 inhibitors act similar to Top1 inhibitors at trapped DNA−enzyme complexes, although there are also differences.60,62−64 Importantly, the trapping of both DNA−PARP complexes and DNA−Top1 complexes elicits cell-killing effects primarily through the conversion of unrepaired SSBs into lethal DSBs. The cytotoxicity of Top1 inhibitors does not require HRR deficiency, although deficient HRR can sensitize cells to these compounds. In most cases, however, the cytotoxicity of PARP-1 inhibitors requires HRR deficiency, either due to mutations in BRCA1/2 or due to other effects. This difference does not appear to be fully explained by the described DNA−enzyme trapping mechanism. PARP-1 plays roles in multiple types of DNA repair, including BER, HRR, nonhomologous end-joining (NHEJ), alternative NHEJ (Alt-NHEJ) (Figure 2), and nucleotide excision repair (NER). 9579



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inhibitors have focused on their DNA repair inhibition, some unrelated anticancer mechanisms are emerging. PARPs have extensive target substrates, specifically, 291 proteins have been experimentally identified to be PARylated with PAR antibodies and 746 PAR-modified proteins have been predicted in silico.69 The poly(ADP-ribose)ylation (PARylation) of target proteins inhibits their interactions with other binding partners (proteins and nucleic acids), serves as interaction scaffolds to recruit other related proteins, and/or triggers their ubiquitination and subsequent degradation.69 In addition to its function in DNA repair, PARP-1 has been consistently reported to be involved in various biological processes, including chromatin remodeling, transcriptional regulation, hypoxic response, angiogenesis, epithelial-mesenchymal transition (EMT), and cancer metastasis.69 Most of these processes are related to tumorigenesis and progression, possibly explaining the anticancer mechanisms of PARP-1 inhibitors that are unrelated to DNA repair. PARP-1 functions in chromatin remodeling, possibly by PARylating histones, the chromatin remodeling factors that facilitates chromatin transcription (FACT), imitation SWItch (ISWI), and the lysine-specific histone demethylases (KDM)5B and KDM4D.5 Among other functions, such chromatin remodeling facilitates the access of transcription factors to DNA and the loading of RNA polymerase II machinery on related promoters.69,70 PARP-1 also functions as a transcriptional coregulator by PARylating several transcription factors to activate or repress related gene transcription. Such PARylated transcription factions include circadian locomotor output cycles kaput (CLOCK), hypoxia-inducible factor (HIF), nuclear factor kappa B (NF-κB), nuclear factor of activated T-cells (NFAT), Snail, Smad, Sp1, and Sox2. Importantly, most of these transcription factors are implicated in carcinogenesis.5,69,70 Of these transcription factors, it is notable that HIF plays a central role in regulating hypoxic response and angiogenesis in cancer. HIF is a heterodimer of HIF-α and HIF-β. The PARP-1-driven PARylation enhances the stability and accumulation of HIF-1α and HIF-2α as well as the transcriptional activity of the HIF coactivator p300. In this way, PARP-1 modulates the transcription of many genes, including VEGF. The protein product of the VEGF gene, VEGF, is the most potent angiogenesis stimulator. Therefore, the PARP-1− HIF−VEGF pathway promotes cancer angiogenesis.69 In addition, PARylation of the transcription factor Snail-1 by PARP-1 increases the former’s stability, promotes the expression of vimentin, a well-known marker of EMT, and stimulates cancer progression to metastasis.71 In fact, many other transcription factors, such as Smad3 and Smad4, are also similarly regulated by PARP-1 and are involved in EMT. Therefore, PARP-1 can stimulate tumorigenesis and malignant progression by regulating chromatin remodeling and gene transcription. It is worth noting that these functions of PARP-1 may be gene-specific, cell type-specific, and/or cell statespecific.70,71 PARP-1 inhibitors have been revealed to suppress the PARP1-mediated processes described above. VEGF-induced angiogenesis was repressed by PARP-1 inhibitors.70 Treatment with the PARP inhibitor 1471 (PJ-34, Figure 3) or 2 was reported to increase the degradation of Snail-1, downregulated vimentin levels, disrupted EMT, and thus impaired the metastatic capacity of melanoma cells. Different PARP-1 inhibitors have also been shown to counteract the Smad3- and Smad4mediated EMT phenotype and thus prevent the metastasis of melanoma cells.69 Therefore, the anticancer and/or antimeta-

Figure 3. Chemical structures of 14 and 15.

static activities of PARP-1 inhibitors likely result from these activities of PARP-1 that are unrelated to DNA repair. In conditions of functional HRR machinery, PARP-1 inhibitors have been consistently shown to elicit therapeutic effects both in clinical trials and in vitro.72

4. NON-BRCA MUTATION BIOMARKERS Currently, BRCA mutations are the most reliable, feasible biomarkers used to select patients for cancer therapy with PARP-1 inhibitors. Actually, a molecular companion diagnostic test, BRACAnalysis CDx, which detects the presence of BRCA mutations in blood samples, was approved.73 However, BRCA status is not the only relevant biomarker and is not sufficient to predict the therapeutic effects of PARP-1 inhibitors.14,74,75 Here, we define non-BRCA biomarkers of PARP-1 inhibitor sensitivity, which likely predict therapeutic responses to PARP1 inhibitor monotherapy in the absence of loss-of-function BRCA mutations. We have classified potential non-BRCA biomarkers according to their relationships to the HRR pathway and PARP-1 as follows (Figure 2). 4.1. HRR factors and Their Downstream Factors. Increasing evidence shows that in addition to BRCA mutations, other HRR defects could also serve as potential biomarkers to predict the therapeutic responses to PARP-1 inhibitors (Figure 2). These defects include aberrations of the Meiotic recombination 11 (MRE11)−RAD50−Nijmegen breakage syndrome 1 (NBS1) complex (MRN), ATM, and their related proteins and Fanconi anemia (FA) proteins and epigenetic inactivation of BRCA1. MRN induces HRR by activating ATM.76,77 The disruption of MRE11 was shown to impair HRR.78,79 The knockdown of MRE11 or NBS1 sensitized cancer cells to the PARP-1 inhibitor 1578 (KU0058948, Figure 3). Similarly, MRE11deficient cancers showed higher sensitivity to 5.80 MRE11 mutations were found in 30.7% of tested endometrial cancer samples79 and approximately 12% of tested colorectal cancer cell lines.80 ATM can phosphorylate the histone variant H2AX to form γH2AX and trigger cell cycle checkpoints (Figure 2).81,82 The loss of function on this pathway, including ATM, checkpoint kinase (CHK)1, CHK2, and the cyclin B1/cyclin-dependent kinase (CDK)1 complex, was found to cause synthetic lethality with PARP-1 inhibitors.83 ATM deletions made breast cancer cells sensitive to 2.84 The levels of ATM protein were negatively correlated to the sensitivity of gastric cancer cells to 2.85 ATM-deficient lymphoma cells were also highly sensitive to 2.86,87 However, data from 109 patient-derived chronic lymphocytic leukemia samples revealed an inconsistent result.88 Nevertheless, 2 has recently been granted BTD status by the FDA for prostate cancer-harboring ATM aberrations.19 In most cases of sporadic breast or ovarian cancer, BRCA1 is not mutated but is often decreased or absent. The epigenetic inactivation of BRCA1 via promoter hypermethylation was 9580



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1, such as fused erythroblast transformation specific (ETS) genes and forkhead box O (FOXO)3A, display potential as biomarkers. Fusions of ETS genes such as FLI-1, ERG, and ETV-1 are common driving events in Ewing sarcoma and prostate cancer.111 Gene fusions of EWS−FLI1 and EWS−ERG are seen in ∼90% and ∼10% of Ewing sarcomas, respectively. ERG and ETV1 are fused to the TMPRSS2 gene in 50% and 5% prostate cancers, respectively.111 EWS−FLI1 was found to drive PARP-1 expression,112 while TMPRSS2−ERG was shown to interact with PARP-1.111 Recently, EWS−FLI1-driven SLFN11 expression has been demonstrated to be a determinant of Ewing sarcoma sensitivity to PARP inhibitor 4.113 However, clinical trials in patients with either Ewing sarcoma34 or prostate cancer114 failed to confirm the results. Additionally, FOXO3A promotes p21/p27 transcription.115 PARP-1 may reduce FOXO3A levels in two ways. One possibility is a downregulation of the PH domain and leucine rich repeat protein phosphatase (PHLPP)1, leading to an increase in AKT-mediated FOXO3A phosphorylation and, thereby, FOXO3A degradation. The other possibility is the PARylation of kappa B kinase (IKK)γ inhibitors, inducing its degradation, attenuating its inhibition on NF-κB, and thereby repressing FOXO3A expression (Figure 2).116 PARP-1 inhibitors inhibit PARP-1 and enhance the levels of FOXO3A via either of these ways.116 In gastric cancer, the expression status of PARP-1 and FOXO3A was observed to be significantly associated with OS and relapse-free survival. Patients with PARP-1−/FOXO3A+ have more favorable prognoses than those with PARP-1+/FOXO3A−.116 4.4. Other Biomarkers. Other potential biomarkers of PARP-1 inhibitor sensitivity include those that are difficult to classify, such as 53BP1, REV7, and CDK5. Both 53BP1 and REV7 inhibit HRR. The loss of either protein restores HRR and renders resistance to PARP-1 inhibitors in BRCA1deficient cells.117−119 REV7 was shown to be downstream of 53BP1 in coordinating the DSB repair pathway choice in BRCA1-deficient cells.119 Moreover, the loss of these proteins has been found in subsets of breast cancers.117−119 CDK5 was discovered to be a determinant of PARP-1 inhibitor sensitivity in a synthetic lethal siRNA screen.120 Silencing CDK5 was confirmed to result in synthetic lethality with PARP-1 inhibitors.121,122 The genomic loss of the CDK5 gene is observed in approximately 5.5% of breast cancers, and the differential expression of CDK5 is also detected in hepatocellular carcinoma.123−125 Together, all non-BRCA-mutation candidate predictive biomarkers of PARP-1 inhibitor sensitivity, including those mentioned above, require additional evidence, especially clinical data.

found to be significantly associated with lymphovessel invasion, low BRCA1 mRNA expression, loss of BRCA1 protein expression, and shorter OS in TNBC and ovarian cancer.89,90 Unexpectedly, however, no impact of BRCA1 promoter methylation status on PFS and OS was found in HGS-OvCa or breast cancer patients treated with PARP-1 inhibitors.91,92 In addition, defects of FA proteins, including FANCA, FANCC,93 FANCD2,94 and FANCM95 have been reported to contribute to PARP-1 inhibitor sensitivity. Patient-derived FANCA−/− and FANCC−/− head and neck squamous cell carcinomas (HNSCC) cells are highly sensitive to both PARP-1 inhibitors 2 and 14, and gene complementation can reverse such sensitivity.93 FANCD2 reduction results in the increased sensitivity of NSCLC cells to both PARP inhibitors 5 and 6.94 Similarly, FA lymphoblasts with FANCM mutations are hypersensitive to 1595 (Figure 3). 4.2. Factors Regulating HRR Factors. These factors themselves are not components of the HRR pathway but can alter HRR activity by regulating the levels or activities of HRR factors (Figure 2). The following factors show their potential as biomarkers of PARP-1 inhibitor sensitivity. CDK12 orchestrates the transcription of DDR genes, such as BRCA1, ATR, and FANCD2 (Figure 2).96 Disabling its catalytic activity lowered BRCA1 levels in ovarian cancer cells and sensitized the cells to PARP-1 inhibitors.97 Moreover, CDK12 has a high mutation rate in HGS-OvCa and the majority of CDK12 mutations are mutually exclusive with mutations in either BRCA1 or BRCA2.74 Inositol polyphosphate 4-phosphatase type II (INPP4B) inhibits the PI3K/protein kinase B (AKT) pathway. INPP4B loss caused significantly increased sensitivity to PARP-1 inhibitors98 and reduced the protein stability of BRCA1, ATM, and ATR.99 Its loss is found in 40% or more of ovarian cancers as well as in other tumors.98,99 However, phosphatase and tensin homologue (PTEN), another tumor suppressor in the same pathway, was recently confirmed not to be such a biomarker.100,101 Protein phosphatase 2 regulatory subunit B, alpha (PPP2R2A) negatively regulates γH2AX, ATM, CHK1, and CHK2.102 PPP2R2A loss dramatically increases ATM phosphorylation and the activity of CHK2, BRCA1, and RAD51. Blocking PPP2R2A was found to impair HRR and to sensitize tumor cells to PARP-1 inhibitors.103 PPP2R2A downregulation is found in various types of cancers, including NSCLC,103 breast cancer,104 and prostate cancer.105 EMSY binds to BRCA2 in partnership with HP1β. EMSY amplification could mimic BRCA2 deficiency106 and was associated with cellular sensitivity to 3.75 The EMSY gene is amplified almost exclusively in sporadic breast cancer (13%) and HSG-OvCa (17%).106 In contrast, HP1β, a partner protein of EMSY, was shown to promote BRCA1 function107 and HP1β-knockdown cells were hypersensitive to the PARP inhibitor 5.108 The last one is Aurora A that controls mitotic entry. It inhibits RAD51 recruitment to DSBs, impairs RAD51 foci formation, and represses HRR.109 Aurora A overexpression was found to sensitize BRCA-proficient cells to the PARP-1 inhibitor 15.109 Its overexpression is observed in various tumors, including breast, ovarian, and pancreatic cancers.109 4.3. The Target PARP-1 Related Factors. PARP-1 cannot serve as a general biomarker to predict PARP-1 inhibitor sensitivity although PARP-1 is the primary target of PARP-1 inhibitors.60,81,88,110 In contrast, other factors related to PARP-

5. RESISTANCE TO PARP-1 INHIBITORS Currently, PARP-1 inhibitors are primarily used to treat HRRdeficient cancers as monotherapies or HRR-proficient cancers as part of a combination therapy. Cancer cells are able to develop resistance to PARP-1 inhibitors. The possible resistance mechanisms include the following: (a) restoration of HRR function in HRR-deficient cancer cells, (b) decreased expression of the target enzyme PARP-1, (c) increased drug efflux, and (d) others.126−128 However, most of these mechanisms have not been examined in the clinic and require further validation. Nevertheless, these known resistance 9581



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patient-derived bone marrow cells with PARP-1 overexpression were unexpectedly found to be resistant to 2.81 In addition, other lines of evidence reveal that the DNA trapping capacity of PARP-1 inhibitors is highly correlated with their cell killing ability, as discussed above. However, little is known about the relationships between their DNA−PARP-1 complex trapping capacity and drug resistance. 5.3. Increase in Drug Efflux. Many mechanisms exist that can reduce PARP-1 inhibitor levels in cancer cell. Among these mechanisms, increased drug efflux from cancer cells due to the overexpression of drug transporters, especially P-glycoprotein (P-gp), has been considered as a possible mechanism of PARP1 inhibitor resistance.66 P-gp can be inhibited by PAR, and PARP-1 inhibitors could therefore enhance its drug efflux function due to alleviation of the PAR-mediated inhibition.66 Until now, of the PARP-1 inhibitors at late-stage clinical trials, only 2 has been reported as a possible substrate of P-gp.136 Therefore, P-gp-overexpressing cancer cells are significantly resistant to 2 but not to other tested PARP-1 inhibitors.66,136−138 It should be noted that 2 did not persistently induce P-gp expression in human cancer cells, although it did have this effect in a mouse tumor model.136,139 Moreover, the relationships between P-gp overexpression and PARP-1 inhibitor sensitivity/resistance in the clinical setting have not been established. These data indicate that with respect to PARP-1 inhibitor resistance, the clinical value of P-gp overexpression in cancer cells requires further evaluation. 5.4. Other Resistant Factors. Other factors may also contribute to PARP-1 inhibitor resistance. One possibility is that high levels of the transcription factor NF-κB confer drug resistance to 2.140 NF-κB levels have been found to increase in 2-resistant cells, and these cells were sensitive to the NF-κB inhibitor (E)-3-tosylacrylonitrile (BAY 11-7082) and the proteasome inhibitor bortezomib. Bortezomib inhibits the degradation of IκBα and thus enhances its suppression of NF-κB signaling. Moreover, silencing p65, a core component of NF-κB signaling, reverses 2 resistance.140

mechanisms might provide valuable information for the clinical development of PARP-1 inhibitors for cancer therapy. 5.1. Restoration of HRR Function. Mutations in BRCA1 or BRCA2 confer HRR defects to cancer cells, which generally make the cells sensitive to PARP-1 inhibitors. Secondary mutations in the mutated BRCA allele are the most extensively recognized resistance mechanism.126 Such secondary mutations can restore the wild-type BRCA protein coding sequence or encode a new form of BRCA that regains the lost critical Cterminal region. Both types of secondary mutations can produce a recovery of the function of BRCA and HRR and thus result in resistance to PARP inhibitors either alone or in combination.126,128 BRCA secondary mutations have been observed in patients with BRCA-mutated breast or ovarian cancer that was initially sensitive but subsequently resistant to PARP inhibitors, emphasizing the clinical importance of these mutations in cancer therapy. Cancer cells with secondary BRCA mutations may arise from the selective killing properties of PARP-1 inhibitors. Specifically, the inhibitors kill BRCA- and HRR-deficient cells but spare BRCA- and HRR-proficient cells in a large cell population.129 Notably, cells that are resistant to PARP-1 inhibitors are occasionally also cross-resistant to other anticancer drugs, such as platinum-based drugs. In contrast, cancers that are resistant to such chemotherapies might be resistant or sensitive to PARP inhibitors.126,127 Factors other than BRCA secondary mutations that result in this type of drug resistance remain to be identified. In addition, the loss of 53BP1 or REV7 enhances HRR but represses NHEJ. In addition, the loss of either of these proteins may lead to a partially ATM-dependent HRR.119,126 The loss of Ku70/80, DNA-PKcs, or Artemis also impairs NHEJ repair.61,66 The downregulation of the microRNAs miR-9 and miR-182 upregulates BRCA1 expression.130,131 Rad51 activity increases due to loss of miR-9 and Aurora-1 or the activation of PTEN.66 Overexpression of the transcription factor HOXA9 in AML cells132 and the phosphorylation of the ribosomal protein S6 in BRCA1-deficient cancer cells133 inhibits DDR and/or restores defective HRR. All these results have been shown to restore or stimulate HRR and thus lead to resistance to PARP-1 inhibitors in specific conditions. 5.2. Decrease in the Target Enzyme PARP-1. The target enzyme PARP-1 is required for the anticancer activity of its inhibitors. The loss of PARP-1 led to higher than 100-fold resistance to 2 or 6.134 Persistent treatments with temozolomide or 5 resulted in decreased PARP-1 protein levels and resistance to PARP-1 inhibitors in resistant HCT116 cells.66 The microRNA miR-210 inhibits the expression of PARP-1. The level of miR-210 has been found to differ in different developmental stages of breast cancer, suggesting that these different stages may exhibit different levels of PARP-1 and have differential sensitivity/resistance to PARP-1 inhibitors.66,134 It should be noted that such differential sensitivity/resistance might result from cancer progression itself not from the effects of PARP-1 inhibitors themselves. PARP-1 inhibitor resistance due to decreased PARP-1 expression is likely to be correlated with a reduction in its catalytic activity and DNA trapping capacity. PARP-1 has been identified as a mediator of the toxicity of 2,135 and the anticancer effects of this compound require 90% inhibition of PARP-1 enzymatic activity.7 Cancer cells with decreased endogenous PARylation show increased resistance to PARP-1 inhibitors.66,78 These data suggest the importance of PARP-1 catalytic activity to PARP-1 inhibitor resistance. However, AML

6. DESIGN STRATEGIES AND STRUCTURAL TYPES OF PARP INHIBITORS Because of the essential role of PARP-1 in DNA repair, tremendous medicinal chemistry efforts have been devoted to the design of PARP-1 inhibitors with high potency, many of which have been or are being tested in various clinical trials. Recently, an increasing amount of medicinal chemistry efforts are focused on the development of novel PARP-1 inhibitors with diverse structural scaffolds to achieve higher potency, better selectivity, and optimal safety profiles. 6.1. Binding Modes of PARP-1 Inhibitors in Nicotinamide Binding Sites. The binding mode of NAD+ in the PARP-1 catalytic domain was first described by Ruf and coworkers.141 As shown in Figure 4, the NAD+ binding domain of PARP-1, also known as the donor site, is divided into three subdomains, including: (a) the nicotinamide-ribose binding domain (NI site), (b) the phosphate binding domain (PH site), and (c) the adenine-ribose binding domain (AD site) (Figure 4A).141 Most of currently reported PARP inhibitors were designed to mimic the nicotinamide structure and bind competitively with NAD+ at the NI site of the PARP-1 catalytic domain. Nicotinamide and its 3-aminobenzoamide analogues were the earliest PARP-1 inhibitors1 but generally showed low inhibitory potency and off-target side effects. Subsequent medicinal chemistry artwork that restricted the 9582



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of the inhibitors. As some of the medicinal chemistry of these inhibitors was reviewed in 2010,1 we here provide the latest update on the design, optimization, PARP-1/2 selectivity, and further pharmacological profiling of these compounds. 6.2. PARP-1/2 Nonselective Inhibitors. Most of current PARP-1 inhibitors have poor selectivity over PARP-2 due to the high homology of these proteins in the catalytic domain. Structurally, PARP-1/2 nonselective inhibitors can be divided into two subclasses based on the embedded bicyclic or pseudobicyclic lactam pharmacophore. 6.2.1. PARP Inhibitors Bearing a Bicyclic Lactam Pharmacophore. Phthalazinones belong to the earliest PARP inhibitors and were first reported by Banasik and Ueda in 1992.142,143 Although the early compounds showed low potency, subsequent structural modification on this framework yielded numerous potent PARP inhibitors, including the firstin-class PARP inhibitor 2. Although 2 is used in the clinic, not all patients bearing BRCA mutants respond to treatment.38,40 In 2008, Jonkers and co-workers reported that tumors failed to respond to long-term treatment with 2 primarily due to P-gp overexpression.144 To address this issue, AstraZeneca developed a backup compound 11114 (Figure 5) that was structurally similar to 2 but was a poor substrate of P-gp. A long-term treatment with 11 showed that eight of the nine mice with K14cre; Brca1F/F; p53F/F (KB1P) tumor xenografts were not refractory within 300 days. More encouragingly, six of seven KB1P tumor-bearing mice that received 100 days of consecutive 2 treatment acquired drug resistance, whereas compound 11 was well tolerated and the median relapse-free survival was increased from 64 to 132 days.114 Subsequently, this compound entered clinical trials to treat solid tumors and the phase I study (NCT01247168) was recently completed. To discover small molecules that could block centrosome clustering for cancer therapeuty, Johannes and cowokers screened the NAD+ mimics of phthalazinone and quinaolinone compounds in their home library. Compound 17145 was the most potent compound in their screen, with IC50 value 1 nM (PARP-1), and it showed very potent centrosome declustering activity in HeLa cells (EC50 < 18 nM). Further optimization of compound 17 for improved declustering potency and PK

Figure 4. Binding modes of PARP-1 inhibitors in nicotinamide binding sites. (A) NAD+ binding domain and subdomains of PARP-1/ 2 proteins. (B) Binding mode of PARP-1 inhibitors bearing a lactam bicyclic pharmacophore or a pseudobicyclic pharmacophore.

rotation of the amide side chain of the 3-aminobenzoamide template led to bicyclic lactam amides (e.g., 2,8 3,25 and 628) or pseudobicyclic amides (e.g., 426 and 527). These secondgeneration PARP-1 inhibitors exhibited much higher PARP-1 potency and selectivity. In both types of inhibitors, the amido function forms a critical H-bond network with the Gly and Ser residues. The π−π stacking formed between the ring-A (green) and the Tyr residue is also essential. In addition, a long chain (Figure 4B) or a short chain (Figure 4B) is generally required to connect the NI binding and AD binding units. This chain is also important for the potency and physicochemical properties

Figure 5. New PARP-1 inhibitors bearing a phthalazinone scaffold. 9583



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Figure 6. PARP-1 inhibitors bearing the pyrrolo[1,2-a]pyrazinone or dimethylpyridazin-3-one scaffold.

Figure 7. PARP-1 inhibitors by modification of the phthalazinone scaffold.

profiles resulted in compound 18,145 with IC50 value 1 nM (PARP-1) and EC50 = 53 nM (declustering). Compound 18, which is a PARP-1, -2, -6 multiple inhibitor with high potency of declustering and with excellent rat oral bioavailability, was suitable for further srudy. Because phthalazinone analogues, including 2, generally have poor aqueous solubility and low bioavailability, efforts were also conducted to directly modify this framework. In 2010, Pescatore and co-workers146 designed a class of new PARP-1 inhibitors bearing a pyrrolo[1,2-a]pyrazine-1(2H)-one scaffold. Among these, compound 19146 was identified as exhibiting high PARP-1 inhibitory potency (IC50 = 1.8 nM). However, this compound failed to show any cytotoxicity against BRCA1deficient cells at a concentration of 20 μM. It was found that substituents on the pyrrole fragment and simultaneous introduction of a piperazine or piperidine moiety as the side chain improved potency. The dichloro-substituted analogue 20146 exhibited an IC50 of 2.1 nM against PARP-1 and a cellular potency (CC50) of 53 nM against BRCA1-deficient cells. Similarly, the [6,5]-spirobicyclic compound 22146 showed similarly high potency both against the PARP-1 enzyme and BRCA1-deficient cells. In contrast, other spirobicyclic congeners146 (21, 23) have much reduced cellular potency. Unfortunately, compounds 20 and 22 displayed high plasma clearance in rats (20, CL > 200 mL/min/kg; 22, CL = 130 mL/ min/kg), preventing the analysis of these compounds in further studies. Replacing the pyrrole motif in compounds 20 and 22 with a dimethylpyridazin-3(2H)-one skeleton led to compounds 24147 and 25147 (Figure 6). Both of the compounds retained high potency against PARP-1 enzyme, but their effects varied

significantly in a cellular assay. Compound 24 retained enzymatic and cellular potencies that were nearly as high as those of the parent compound 22 but still suffered from high plasma clearance (CL = 57 mL/min/kg). Further introducing a para-fluoro benzyl group into the side chain afforded compound 26,147 which retained high PARP inhibitory potency (3.6 nM). This compound showed much improved cellular activity against BRCA1-deficient cells, with a CC50 value of 9.1 nM. Unfortunately, the metabolic instability and high intrinsic clearance of the parent compound were not improved.147 Zhu and co-workers148 at Abbott reported another example of modifying the phthalazinone template and generated a series of tetrahydropyridopyridazinone analogues. It was proposed that replacement of the phenyl moiety in the phthalazinone scaffold with a piperidine ring would provide an additional water-mediated H-bond between the piperidine NH and Glu988 in the NI site of PARP-1. In this way, the water solubility of the new inhibitors would be enhanced. Although the initial compound 27148 showed only a moderate potency (Ki = 118 nM), the subsequent addition of an N-pyridinyl piperazine side chain through the benzoic linker generated the highly potent PARP-1 inhibitor 28.148 This compound exhibited a potency of 1 nM both against PARP-1 enzyme and BRCA1-deficient cells (Figure 7). In murine B16F10 syngeneic melanoma xenografts, which were relatively resistant to most chemotherapeutics, a low dose of compound 28 (1.25 mg/kg) in combination with temozolomide (50 mg/kg) showed significant antitumor efficacy and no body weight loss. Recently, Zheng and Wang149 reported that replacement of the pendant fluorobenzyl linker in 2 with a thienyl moiety has no effect on PARP-1 inhibitory potency. Interestingly, the 9584



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wild-type BRAF stage 4 or unresectable stage 3 melanoma (NCT01605162). In 2014, the same company reported a phase I study of the PARP inhibitor 7 (E7449), which has IC50 values of 1.0 nM against PARP-1 and 1.1 nM against PARP-2 (Figure 8).29 The MTD of 7 was 600 mg/kg once daily when used as a single agent in advanced solid tumor patients. The partial response was 7.1% (n = 2, both with ovarian cancer), and 46.4% of patients had durable stable disease (≥23 weeks). The PK profile indicated that 7 was rapidly absorbed at a single dose, with a Tmax of 1.5 h and an elimination half-life of 8 h. Significant inhibition of PARP was observed at all doses, ranging from 50 to 600 mg. This compound is now undergoing both phase I and phase II studies as a single agent or as part of a combination with a cytotoxic agent for advanced solid tumors or B-cell malignancies (NCT01618136). In addition, Li and coworkers recently reported more analogues by replacement of the isoindoline moiety in the side chain with various aryl or heteroaryl groups; however, none of these compounds were more potent than 7.152 A scaffold-combining strategy was reported by BioMarin Pharma, eventually leading to the discovery of 6,28 the most potent clinical PARP-1 inhibitor. The initial effort to combine the benzimidazole 30 and phthalazinone 16 cores yields a tricyclic phthalazinone derivate 3128 that has high potency against PARP-1, with an IC50 of 6.1 nM (Figure 9). Subsequent structural optimization by replacing one phenyl ring with a triazole moiety to improve aqueous solubility and introducing two fluoro atoms to enhance cellular potency affords the final compound 6.28 The stereochemistry is found to play an essential role, and the isomer 6 (BMN673) was found to be 240- and 340-fold more potent than its enantiomer 3228 (BMN674) in PARP-1

introduction of another thienyl moiety in the side chain generated compound 29,149 which is highly potent, possessing an IC50 value of 10.8 nM. Docking studies revealed that the thienyl moiety in the side chain formed a new π−π interaction with Arg 217. Compound 8 (GPI 2116, Figure 8) was a tetracyclic PARP-1 inhibitor developed by Eisai (formerly MGI Pharma).59,150 This

Figure 8. PARP-1 inhibitors by modification of the tetracyclic isoquinolones scaffold.

compound has a Ki value of 50 nM against PARP-1 and showed significantly enhanced chemosensitivity in a p388 leukemia model in B6D2F1 mice when used in combination with cisplatin.150 Systematic in vitro and in vivo tests indicated that treatment with a combination of 8, temozolomide, and irradiation results in a longer life span compared to temozolomide or irradiation alone. A phase I trial was subsequently conducted, and for patients with advanced solid tumors, the MTD of 8 was established as 4 mg/kg (po, days 1− 7) in combination with temozolomide at 150 mg/kg (po, days 1−5) for a 28-day dosing cycle.151 A phase II study of 8 in combination with temozolomide is ongoing in patients with

Figure 9. Discovery of the highly potent clinical PARP-1 inhibitor 6 and its cocrystal structure with the catalytic domain of PARP-1 (PDB code: 4PJT). 9585



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Figure 10. PARP-1 inhibitors bearing a dihydroquinolin-2(1H)-one core.

Figure 11. PARP-1 inhibitors bearing a tetrahydroisoquinolin-1-one core.

3,4-Dihydroquinolin-2(1H)-one and its derivatives are also reported as pharmacophores of PARP-1 inhibitors to interact with the catalytic domain, similar to phthalazinones. Fusing a thiopyrano ring to this scaffold provided compound 33157 with an IC50 value of 42 nM against PARP-1 and a cellular potency of 220 nM (Figure 10). PK studies on this compound showed that it had a relatively long intravenous half-life (t1/2 = 3.45 h), AUC concentration (2908 h·ng/mL), and acceptable clearance (3.4 L/h/kg) at 10 mg/kg in rat. Good metabolic stability (t1/2 = 52.6 min) was also detected in human liver microsomes. Meanwhile, compound 33 has a high brain/plasma ratio of 0.64−0.72 over 4 h. Starting from 3,4-dihydroquinolin-2(1H)-one 34,158 Gangloff and co-workers conducted a structural modification to afford compound 35,158 showing (a) an IC50 value of 76 nM for PARP-1 inhibition and (b) optimal cellular activity, with a chemopotentiation factor of approximately 4300. Compound 35 significantly inhibited PAR synthesis in a SW-620 tumor xenograft model. However, this compound suffered from unacceptable hERG inhibition (>97% at 10 μM). Fusing a pyrrole or thiophene moiety to the dihydroquinolin-2(1H)-one template leads to diverse tricyclic derivatives, among which compound 36159 has an IC50 value of 44 nM. Further

enzymatic and cellular assays, respectively. The X-ray cocrystal structure of PARP-1 catalytic domain with 6153 shows that the fused tricyclic core not only retains all the key interactions as that the phthalazinone core in 2 but also provides for more additional direct or indirect interactions, including H-bonds and π−π stackings. Compound 6 is a highly potent PARP-1 inhibitor, with an IC50 value of 0.57 nM, and significantly inhibited H2O2-elicited PAR synthesis in vitro (IC50 = 2.5 nM). In addition, 6 was exhibited at least 18-fold selectivity in killing tumor cells carrying BRCA gene or PTEN gene defects.154 Recent studies further revealed that the high potency of 6 may be partially relevant to its high PARP-trapping capacity at the SSB sites. Furthermore, 6 has good oral bioavailability (>40% in rats), optimal plasma exposure, and a long half-life (t1/2, approximately 40 h). At an oral dose of 0.33 mg/kg once daily for 28 days, 6 significantly inhibited the growth of BRCA-1 mutant MX-1 tumor xenografts in mice. In these experiments, four of six mice achieved a complete response. On the basis of the promising preclinical results, compound 6 is being investigated in a number of clinical trials either alone155,156 or i n c o m bi n a t i o n ( N C T 0 2 0 4 9 5 9 3 , N C T 0 2 3 5 8 2 0 0 , NCT02116777, and NCT02317874). 9586



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modification from a six- to a seven-membered lactam leads to a decrease of PARP-1 inhibition potency for 37;159 however, the thiophene-fused compound 38159 retains similar potency as that of 36 (Figure 10). Unfortunately, both 36 and 38 fail to exhibit significant antiproliferative effects in BRCA mutant cells. Through a scaffold hopping strategy, Zhang and co-workers use a tetrahydroisoquinolin-1-one skeleton that is commonly seen in dopamine receptor ligands to mimic the phthalazinone scaffold of 2 to interact with the PARP-1 catalytic domain.160 First, they introduce a bicyclic amino side chain to this tricyclic scaffold through an acetamido moiety as the linker. However, most compounds derived from 40160 only show marginal PARP-1 potency. Further modifications on both the side chain and the linker lead to significantly improved potency. The representative compound 41160 bears a flexible linker, whereas compound 42160 has a bulky linker. These two compounds showed PARP-1 IC50 values of 19 and 0.31 nM, respectively. In addition to excellent enzymatic potency, compound 42 displayed a CC50 value of 96 nM against BRCA2-deficient VC8 cells. Interestingly, further modification on the tricyclic core generated compound 43,160 bearing both tetrahydrocyclopenta[ij]isoquinolin-7(1H)-one and phthalazinone frameworks. This compound showed equally high potency against both PARP-1 and the BRCA2-deficient V-C8 cell (IC50 = 3.46 nM, CC50 = 4.53 nM). Even higher potency was observed in BRCA1deficient MDA-MB-436 cells (Figure 11). Mechanic studies revealed that the new PARP-1 inhibitor 43 significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Recently, Giannini and co-workers161 identified a class of new PARP-1 inhibitors bearing a quinazolinone pharmacophore through a virtual screening approach. Representative compound 44161 shows high PARP-1 potency (IC50 = 9.8 nM), but the cellular potency is moderate (EC50 = 256 nM). Tumor growth inhibition was 47% at 200 mg/kg in BRCA1-deleted and BRCA2-mutated MX1 human breast carcinoma xenografts. Recently, quinazolinedione analogues were reported as PARP-1 inhibitors. Compound 45161 has a flexible linker and shows an IC50 value of 120 nM against PARP-1, with a nearly equal potency against PARP-2 (70 nM). Further modification on this scaffold affords compound 46,162 which shows much improved PARP-1 potency, with an IC50 of 9.51 nM. However, this compound does not show noticeable potency in a cellular assay (Figure 12).162 In the meantime, a more potent PARP inhibitor 47163 is developed by the same group showing an IC50 value of 1.29 nM against PARP-1, almost 8-fold less potency against PARP-2 (11.3 nM). Mechanic studies reveal that compound 47 raises the level of DNA damage, induces G2/M arrest and cell death, and exerts a chemosensitizing effect on BRCA proficient cancer cells. The MX-1 xenograft tumor model shows that compound 47 (25 mg/kg) in combination with TMZ (50 mg/ kg) could remarkably inhibit the growth of tumor without aggravating side effects. 6.2.2. PARP-1 Inhibitors Bearing a pseudobicyclic Lactam as the Pharmacophore. On the basis of the promising results of the clinical PARP-1 inhibitor 5, which bears a pseudobicyclic lactam pharmacophore, more efforts to optimize this scaffold were recently conducted. Imidazo[4,5-c]-pyridine carboxamide 48164 was found to have an IC50 value of 528 nM (Figure 13). Further studies showed that the combination of compound 48 (25 mg/kg) with cisplatin (2 mg/kg) had similar antitumor

Figure 12. PARP-1 inhibitors bearing a quinazolinone or quinazolinedione core.

efficacy as a combination of compound 5 (25 mg/kg) and cisplatin (2 mg/kg) in a A549 mouse model. Recently, dihydrobenzofuran carboxamides were reported to show PARP-1 activity as well. Representative compound 49165 has an IC50 value of 114 nM (Figure 13) but only showed marginal activity in BRCA2-deficient DT40 cells. 7-Azaindole1-carboxamides are an additional series of PARP-1 inhibitors bearing a pseudobicyclic lactam. Among these compounds, 50166 is the most potent, with an IC50 of 70 nM (Figure 13). Compared to 2, compound 50 shows higher sensitivity against resistant, P-gp-overexpressing cells. At a dose of 100 mg/kg, 50 showed similar antitumor growth inhibition of the MX-1 human breast carcinoma xenografts as 2 at a dose of 167 mg/kg and no death or significant body weight loss were observed.166 6.3. Efforts on the Development of Selective PARP-1 or PARP-2 Inhibitors. In 2006, Hattori and co-workers167 identified a series of quinazolinone analogues that showed moderate PARP-1 selectivity over PARP-2, ranging from 9- to 39-fold selectivity. The representative compound 51167 has IC50 values of 13 and 500 nM for PARP-1 and PARP-2, respectively. The cocrystallization structure of the methyl analogue 52142 with the PARP-1 catalytic domain indicated that the PARP-1/2 selectivity is likely due to an insertion of the side chain’s pyridinyl motif into the pocket containing amino acids Asn 767, Asp 770, Asp 796, Asn 868, and Ala 880. In this way, the pyridinyl motif forms van de Waals interactions in the AD site. Interestingly, further modification leads to the quinoxaline derivative 53167 that shows reversed PARP-1/2 selectivity. This compound has an IC50 value of 8 nM against PARP-2 and is more than 10-fold more potent than against PARP-1. Compounds bearing an isoquinolindione core also preferably interact with PARP-1. The representative compound 54168 shows an IC50 value of 45 nM and more than 80-fold PARP-1/ 2 selectivity (Figure 14). Many efforts169,170 were also devoted to the structural modification of isoquinolinones as selective PARP-2 inhibitors. This class of compounds is generally less potent than other reported PARP-2 inhibitors. The most potent compound is 55,169 bearing a benzamido moiety but only showing moderate PARP-2 potency (1.5 μM). However, this compound was still nearly 10-fold more potent against PARP-2 than against PARP1. 9587



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Figure 13. PARP-1 inhibitors bearing a pseudobicyclic lactam core.

Figure 14. Selective PARP-1 or PARP-2 inhibitors bearing a quinazolinone or isoquinolinone core.

Figure 15. Selective PARP-1 inhibitors bearing anisoindolinone core and cocrystal structure of 60 with PARP-1 (left) (PDB code 5A00) and PARP2 (right) (PDB code 4ZZY).

Recently, Papeo and co-workers171 reported a high throughput screening and subsequent structural optimization effort that led to a series of isoindole-4-carboxamides that showed moderate PARP-1/2 selectivity. The representative compounds 56171 and 57171 showed IC50 values of less than

100 nM and were slightly selective against PARP-1 over PARP2. The cocrystal structure showed that the pseudo sevenmembered lactam ring in these compounds formed an Hbonding network and π−π stacking in the PARP-1 catalytic domain. On the basis of this analysis, further structural 9588



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modification focusing on the side chain yields compound 58,171 which shows a PARP-1 KD value of 30 nM and is >87-fold selective over PARP-2 (Figure 15A). This compound also shows high inhibitory potency against PARylation. However, high clearance (230 mL/min/kg) and poor oral bioavailability are also observed. Further optimization of the side chain, especially the introduction of a difluoro-substituted cyclohexyl moiety, significantly improved the PK parameters. Among these compounds, compounds 59171 and 60171 both retain high PARP-1 potency and selectivity and show significantly reduced plasma exposure and a much elevated bioavailability (Figure 15A). At an oral dose of 150 mg/kg once daily, compound 60 alone elicits significant tumor growth inhibition in BRCA1-mutated MDA-MB-436 human tumor xenograft models. When used as part of a combination, compound 60 (100 mg/kg) combined with temozolomide (50 mg/kg) also results in high antitumor growth inhibition, with three out of six mice showing complete tumor regression.171 From the cocrystal structures with the catalytic domains of both hPARP-1 and hPARP-2 (Figure 15B,C), both 59 and 60 form the same H-bonding networks with the Gly (Gly 863 for PARP-1, Gly 429 for PARP-2) and Ser (Ser 904 for PARP-1, Ser 470 for PARP-2) moieties as well as π−π stacking with Tyr (Tyr 907 for PARP-1, Tyr 473 for PARP-2) in the NI sites of PARP-1 and PARP-2.171 Meanwhile, the 4,4-difluorocyclohexylpiperidinyl moiety is found to insert deep within the AD site and allow the 4,4-difluorocyclohexyl ring, in combination with the slightly dissimilar orientation of the α-helix in the two proteins, to induce a larger pocket in PARP-1 that is able to better accommodate the 4,4-difluorocyclohexyl moiety.

sensitivity/resistance, and (c) to identify and validate druggable targets whose inhibitors might elicit synthetic lethality when combined with PARP-1 inhibitors. Making the best of these opportunities is likely to further expand the clinical uses of PARP-1 inhibitors, allow their therapeutic application in more precise patient populations, and produce higher efficacy and/or lower toxicity. However, there are also major challenges that remain, including our limited knowledge regarding the functions of many DDR genes, possible interactions between them and, particularly, their relationships to PARP-1 and its inhibition. 7.2. Discovering and Validating Biomarkers of PARP-1 Inhibitor Sensitivity. Correctly identifying patients with PARP-1 inhibitor-responsive cancers is critical for successful cancer therapy, particularly with single-agent PARP-1 inhibitors. It is important to select patients according to specific biomarkers rather than the tissue types of their cancers.101 At present, despite their limited prediction ability, BRCA1/2 mutations are essentially the only two biomarkers of PARP-1 inhibitor sensitivity that can be used as the basis of selection for patients. Nevertheless, more than 20 non-BRCA potential biomarkers of the PARP-1 inhibitor sensitivity have been reported and many more will certainly be identified. These studies provide important clues for the discovery of new biomarkers; however, most biomarkers are derived from basic research and lack critical validation in clinical trials. In addition to continuously searching for potential biomarkers of PARP-1 inhibitor sensitivity, therefore, more efforts are needed to evaluate the predictive power of the reported candidate biomarkers in the clinic or in clinical trials. Systematically analyzing the frequencies of biomarker aberrations in cancer patients is also helpful for patient selection. Considering the limited prediction value of any single biomarker, such as loss of BRCA1 or BRCA2, combinations of two or more candidate biomarkers should be tested to further enhance their ability to predict PARP-1 inhibitor responsiveness. 7.3. Understanding and Overcoming PARP-1 Inhibitor Resistance. The clinical use of PARP-1 inhibitors to treat cancers has a short history, and there is only a limited understanding regarding the characteristics and mechanisms of cancer resistance to PARP-1 inhibitors. Most of the current knowledge of PARP-1 inhibitor resistance comes from preclinical studies, especially in vitro studies. However, clinical resistance to PARP-1 inhibitors will be inevitable, just as is the case for other anticancer drugs. Moreover, PARP-1 inhibitors are likely to be used to treat cancers that harbor different genetic defects. Therefore, the following issues regarding the clinical resistance to PARP-1 inhibitors need to be further explored, including: (a) drug resistance in cancers with different genetic defects, (b) tumor resistance to different PARP-1 inhibitors, (c) potential biomarkers of PARP-1 inhibitor resistance in different contexts, (d) overcoming PARP-1 inhibitor resistance, and (e) clinical therapeutic regimens that prevent and/or delay the emergence of inhibitor resistance. However, some issues will be difficult to address by using PARP-1 inhibitors alone, such as so-called secondary mutations in BRCA1/2, which are believed to restore HRR function. Such secondary mutations likely exist in very few cancer cells that are insensitive to PARP-1 inhibitors but can expand to become the predominant cell population after BRCA mutant cells that are sensitive to PARP-1 inhibitors are killed.56 Therefore, secondary mutations are not likely to be remutations in mutated BRCA1/2 alleles within PARP-1 inhibitor-sensitive

7. OPPORTUNITIES AND CHALLENGES IN PARP-1 INHIBITORS FOR CANCER THERAPY Since 2010, many important advances in the field of PARP-1 inhibitors for cancer therapy have been achieved. As described above, the most important of these advances is the approval of 2 as the first in-class PARP-1 inhibitor to be used to treat ovarian cancer harboring BRCA1/2 mutations. This breakthrough has reignited great interest in PARP-1 inhibitors. From basic research to development and to clinical applications, such successes have paved a new avenue for more extensive, deeper investigations of PARP-1 inhibitors. Simultaneously, various challenges are also emerging. 7.1. Exploiting DDR Defects. There are at least 450 reported DDR genes, 40% of which encode enzymes, which is higher than the proportion of tumorigenic enzyme-encoding genes (25−30%).172 Germline defects in 58 DDR genes are related to cancer predisposition. Somatic mutations or alterations of DDR genes can also contribute to tumorigenesis and tumor progression.172 PARP-1 inhibitors that inhibit BER, block the recently recognized Alt-NHEJ pathway, and/or derepress NHEJ exert synthetic lethality with HRR defects (e.g., BRCA loss-of-function mutations), causing selective anticancer activity (Figure 2). Abnormal alterations of more than 20 DDR-related genes have been determined to be potential determinants of PARP-1 inhibitor sensitivity (Figure 2), and more will certainly be identified. These facts reveal that among the numerous DDR genes, there are abundant opportunities (a) to exploit potential defects in the DDR pathway to induce synthetic lethality via PARP-1 inhibition, (b) to discover more predictive biomarkers of PARP-1 inhibitor 9589



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with most of these drugs, however, PARP-1 inhibitors did not give rise to the expected clinical benefits, as shown by the examples of combination therapies with 2 (Supporting Information, Table 1). In sharp contrast, the PARP-1 inhibitor 2 significantly improved clinical benefits when used with a microtubule inhibitor (paclitaxel) or an angiogenesis inhibitor (cediranib), although these drugs are not classically DNAdamaging agents. Recently, paclitaxel has been shown to disrupt intracellular trafficking of DNA repair proteins, including ATM, on interphase microtubules. This effect could further increase the accumulation of DNA damage due to the inhibition of SSB repair by 2.175 This effect is a possible cause of the improved efficacy of the 2 plus paclitaxel combination observed in gastric cancer with low levels of ATM.76 Angiogenesis inhibitors normally cause hypoxia, which leads to defects in DNA repair by interfering with the expression of DNA repair factors.176 Low BRCA1 expression might be an effective response predictor for the EGFR inhibitor treatment in NSCLC,177 and 2 can attenuate and/or prevent BRCA1 expression.178 From the viewpoint of mechanistic synergism, 2 should achieve better therapeutic effects in combination with DNA-damaging agents than with other anticancer drugs. However, more promising effects were seen in combinations containing paclitaxel or cediranib even though both of these drugs only caused weak interferences with DNA repair (Supporting Information, Table 1). One possible reason for this result is that patients could not tolerate the enhanced toxicity of the combination of 2 and DNA-damaging agents due to severe DNA damage. The examples mentioned above reveal that balancing enhanced therapeutic effects with increased toxicities in order to achieve maximal clinical benefit is the predominant issue in designing rational combination regimens with PARP-1 inhibitors. Drugs that mildly interfere with DNA repair might be more useful as PARP-1 inhibitor combination partners. On the other hand, tumor drug resistance is another important issue that should be taken into account in designing combination therapy. Drugs that can overcome and/or delay tumor resistance to PARP-1 inhibitors (or drugs with resistance mechanisms that can be overcome and/or delayed by PARP-1 inhibitors) are potential combination partners for PARP-1 inhibitors. Such drugs deserve persistent exploration as possible combination partners with PARP-1 inhibitors, and the molecular mechanisms of these combinations should be thoroughly studied. 7.6. Developing Next-Generation PARP Inhibitors for Cancer Therapy. The PARP-1 inhibitors that are currently approved or are in late-stage clinical trials have the following common features: (a) their PARP-1 inhibition is not selective, (b) they can induce tumor drug resistance against which there is no effective strategy, and (c) they are used in combination therapies that are plagued by uncertainties concerning the selection of the proper partner, principally with respect to therapeutic effects, toxicity, and drug resistance. Such uncertainties increase the complexity and unpredictability of these combination therapies. Therefore, the development of next-generation PARP inhibitors for cancer therapy is becoming necessary. Next-generation PARP inhibitors might include inhibitors that (a) can highly selectively inhibit PARP-1 or other members of the PARP family, (b) can overcome tumor resistance to present PARP inhibitors, and (c) might concurrently inhibit PARP and other validated anticancer targets, the inhibitors of which have been proven to be clinically

populations. Rather, such BRCA1/2 mutations are likely to be inherent in a subset of cancer cells that are insensitive to PARP1 inhibitors. To prevent and/or delay the occurrence of tumor drug resistance in the clinic, combinations of PARP-1 inhibitors and other proper anticancer agents will be necessary, even in treating cancers that are apparently sensitive to PARP-1 inhibitors. 7.4. Enhancing the Selectivity of PARP-1 Inhibitors. All PARP-1 inhibitors that are currently in the late-stage of clinical trials also inhibit its closest isoform, PARP-2, sometimes with higher potency (Table 1). These compounds can inhibit other members of the PARP family as well. For example, both 2 and 5 inhibit PARP-3 and PARP-4 and 3 also inhibits PARP-5a.173 An intensive study was performed with 185 small-molecule inhibitors regarding their ability to bind to the catalytic domains of 13 human PARP family members, including PARP-1 to PARP-5. The data showed that many inhibitors, including 2, 3, and 5, can bind to several PARP family members and inhibit their enzymatic activity.173 In addition, some inhibitors (e.g.,7) can inhibit other signaling pathways (e.g., Wnt signaling).30 Therefore, the inhibitors that are under clinical evaluation are not selective PARP-1 inhibitors and might cause additional, possibly harmful effects. It has been revealed that only the loss of both PARP-1 and PARP-2 can cause embryonic lethality in mice,174 suggesting that inhibiting both PARP-1 and PARP-2 likely causes more severe toxicity than selectively inhibiting either protein. In this regard, developing high selectivity PARP1 inhibitors might be worthwhile, although their anticancer activity possibly decreases due to the overlapping functions of PARP-1 and PARP-2 in DNA repair. Until now, one selective PARP-1 inhibitor (60) has been reported that inhibited PARP1 80-fold more potently than PARP-2 and totally repressed the growth of MDA-MB-436 tumor xenografts.171 These results indicated that development of selective PARP-1 inhibitors might be a promising approach. 7.5. Persistently Exploring Rational Combination Therapy to Expand the Patient Population. Current evidence shows that PARP-1 inhibitors alone might be clinically effective only in cancers that harbor defective HRR, as described above and as demonstrated by the effects of 2 (Table 2). Relatively low incidence of HRR deficiencies limits the anticancer uses of PARP-1 inhibitors. The combination of PARP-1 inhibitors with other anticancer drugs has been revealed to not only improve their therapeutic efficacy but also to extend their treatments to HRR-proficient cancers. In this way, the patient population that can benefit from PARP-1 inhibitors can be expanded. Examples of such combinations with 2 are shown in Supporting Information, Table 1. Moreover, combination therapy is a classical therapeutic mode for the majority of cancers and anticancer drugs. Therefore, exploring the combination therapy of PARP-1 inhibitors becomes necessary for their clinical development. In exploring their combination therapy in clinical trials, the greatest challenge might be that the ideal combination regimens cannot be effectively determined based on the known mechanisms of action of candidate anticancer drugs. For instance, the anticancer potentiation of PARP-1 inhibitors is primarily correlated with their inhibition of SSB repair, which amplifies the DNA-damaging effects of anticancer drugs.3 Some chemotherapies, including platinum drugs (carboplatin and cisplatin), Top I inhibitors (topotecan), and alkylating agents (dacarbazine and temozolomide), all elicit SSBs that are repaired in part by PARP-1-mediated BER. When combined 9590



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effective in combination with existing PARP-1 inhibitors. Fortunately, the first selective PARP-1 inhibitors have been designed based on available structural knowledge and design strategies. This result, together with further clinical trials, will fuel more efforts in the pursuit of more selective and safer PARP-1 inhibitors. Meanwhile, efforts to discover additional types of PARP-1 inhibitors are also urgently needed given that resistance against PARP-1 inhibitors that are used extensively in the clinic will unavoidably occur. The use of additional types of inhibitors might simplify combination therapies with existing PARP inhibitors and other anticancer drugs, reducing uncertainty and enhancing reliability.

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rational design and syntheses of biologically active small molecules and their chemical biology. Ao Zhang received his doctorate in Organic Chemistry in 2000 and performed postdoctoral research in Medicinal Chemistry during 2001−2004 at Georgetown University Medical Center and Harvard Medical School McLean Hospital. In 2004, he was promoted to Research Investigator and Instructor of Harvard Medical School. In 2006, he received the Hundred Talent Project award from the Chinese Academy of Sciences and became the Professor of Medicinal Chemistry at the Shanghai Institute of Materia Medica (SIMM). In 2011, he was awarded the Distinguished Young Investigator Award from the Chinese Natural Science Foundation. He has coauthored more than 100 original articles and reviews. His research interests include the design and synthesis of novel small molecules as structural and functional probes for the diagnosis and treatment of brain disorders and cancers.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b00055.

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Ze-Hong Miao received his Ph.D. degree from the Shanghai Institute of Materia Medica (SIMM) in 2003. He was trained as a visiting fellow at the National Cancer Institute of the National Institutes of Health in the United States from 2004 to 2006. He has been a professor in pharmacology at SIMM since 2007. His research interests are focused on cellular and molecular mechanisms of anticancer compounds, including PARP inhibitors. Several lead compounds for PARP inhibitors were identified in his group as well as in his collaborators’ groups. In addition, a great deal of work has been performed on the structure−activity relationship and structural optimization of these inhibitors. Currently, the preclinical studies on two PARP-1 inhibitors, simmiparib and mefuparib hydrochloride, have been completed.

Olaparib (2) in completed combinatorial studies (PDF)

AUTHOR INFORMATION

Corresponding Authors

*For Z.H.M.: phone, +86-21-50806820; fax, 86-21-50806820; E-mail, [email protected]. *For A.Z.: phone, +86-21-50806035; fax, 86-21-50806035; Email, [email protected].

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Author Contributions ∥

Y.-Q.W. and P.-Y.W. contributed equally to this work.

ACKNOWLEDGMENTS This work was supported by the National Basic Research Program of China (2012CB932502 for Z.H.M. and 2015CB910603 for A.Z.), the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” of China (2016ZX09101009 for Z.H.M.), the National Natural Science Foundation of China (81573450 and 81321092 for Z.H.M. and 81430080 for A.Z.), the Chinese Academy of Sciences (XDA12020104 and Hundred Talents Project for Z.H.M.), the Institutes for Drug Discovery and Development of the Chinese Academy of Sciences (CASIMM0120152003 and CASIMM0120153005 for Z.H.M.), the Science and Technology Commission of Shanghai Municipality (16JC1406300 to Z.H.M., 14431905300 for A.Z.), and the State Key Laboratory of Drug Research (SIMM1601ZZ-03 for Z.H.M.).

Notes

The authors declare no competing financial interest. Biographies Ying-Qing Wang received her Ph.D. in Pharmacology from Jilin University in 2010. After her postdoctoral work in the field of preclinical drug development and cancer research, she joined the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, in 2013, where she has been associate professor of Tumor Pharmacology since 2013. Ping-Yuan Wang received his B.S. in chemistry from Central China Normal University in 2010 and then became a graduate student under the supervision of Professor Guang-Fu Yang at the Central China Normal University. In 2011, he joined Professor Ao Zhang’s group at Shanghai Institute of Materia Medica, Chinese Academy of Sciences, as a joint graduate student. His doctoral thesis focuses on the design and synthesis of novel PARP-1 inhibitors as anticancer treatments.

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ABBREVIATIONS USED AD, adenine-ribose; Alt-NHEJ, alternative nonhomologous end-joining; AKT, protein kinase B; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3 related; BARD1, BRCA1-associated RING domain protein 1; BER, base excision repair; BTD, breakthrough therapy designation; Cdc25, cell division cycle 25; CL, clearance rate; CLOCK, circadian locomotor output cycles kaput; DDR, DNA damage response; DNA-PKcs, catalytic subunit of the DNA-dependent protein kinase; DSB, double-strand breaks; EMT, epithelial−mesenchymal transition; ETS, erthroblast transformation specific; FA, Fanconi anemia; FACT, facilitates chromatin transcription; FOXO, Forkhead box O; HGS-OvCa, high-grade serous ovarian cancer; HIF, hypoxia-inducible factor; HNSCC, head and neck squamous cell carcinomas; HP1, heterochromatin protein 1; HRR, homologous recombination repair; IKK,

Yu-Ting Wang received her Bachelor of Science degree in Pharmaceutical Science from Sun Yat-sen University in 2013 and then became a graduate student under the supervision of Professor ZeHong Miao at Shanghai Institute of Materia Medica, Chinese Academy of Sciences. Guang-Fu Yang obtained his Bachelor of Science degree in Chemistry at Central China Normal University (CCNU) in 1992 and his Doctor of Philosophy in Pesticide Science from Nankai University in 1997. He has worked at CCNU since 1997 and became a full Professor in 2001. He was the Dean of College of Chemistry, CCNU, from 2002 to 2014. Since 2003, he has also been the director of the Key Laboratory of Pesticide & Chemical Biology of the Ministry of Education. In 2014, he was promoted to the Assistant President of CCNU. In 2009, he was awarded the Distinguished Young Investigator Award from National Nature Science Foundation of China. His research interests include 9591



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inhibitor of κ B kinase; INPP4B, inositol polyphosphate 4phosphatase type II; ISWI, imitation switch; KDM, lysinespecific histone demethylase; MMEJ, microhomology-mediated end-joining; MRE11, meiotic recombination 11; MRN, MRE11−RAD50−NBS1 complex; NBS1, Nijmegen breakage syndrome 1; NER, nucleotide excision repair; NFAT, nuclear factor of activated T-cells; NHEJ, nonhomologous end-joining; NI, nicotinamide-ribose; ORR, objective response rate; OS, overall survival; PAR, poly(ADP-ribose); PARP, poly(ADPribose) polymerase; PARylation, poly(ADP-ribose)ylation; PBMCs, peripheral blood mononuclear cells; PFS, progression-free survival; PHLPP, PH domain and leucine rich repeat protein phosphatase; PI(3,4)P2, phosphatidylinositol (3,4) bisphosphate; PIKK, PI3K-related kinase; PLD, pegylated liposomal doxorubicin; Pol θ, polymerase θ; PP2A, protein phosphatase 2A; PPP2R2A, PP2A regulatory subunit B, alpha; PTEN, phosphatase and tensin homologue; γH2AX, phosphorylated histone H2AX; RPA-32, replication protein A-32; SSB, single-strand break; TNBC, triple-negative breast cancer; Top1, topoisomerase I; Vd, distribution volume

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death in tumor cells in culture. Biochem. Pharmacol. 1995, 50, 705− 714. (12) Patel, A. G.; De Lorenzo, S. B.; Flatten, K. S.; Poirier, G. G.; Kaufmann, S. H. Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro. Clin. Cancer Res. 2012, 18, 1655−1662. (13) Ledermann, J.; Harter, P.; Gourley, C.; Friedlander, M.; Vergote, I.; Rustin, G.; Scott, C.; Meier, W.; Shapira-Frommer, R.; Safra, T.; Matei, D.; Macpherson, E.; Watkins, C.; Carmichael, J.; Matulonis, U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N. Engl. J. Med. 2012, 366, 1382−1392. (14) Ledermann, J.; Harter, P.; Gourley, C.; Friedlander, M.; Vergote, I.; Rustin, G.; Scott, C. L.; Meier, W.; Shapira-Frommer, R.; Safra, T.; Matei, D.; Fielding, A.; Spencer, S.; Dougherty, B.; Orr, M.; Hodgson, D.; Barrett, J. C.; Matulonis, U. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014, 15, 852−861. (15) Gelmon, K. A.; Tischkowitz, M.; Mackay, H.; Swenerton, K.; Robidoux, A.; Tonkin, K.; Hirte, H.; Huntsman, D.; Clemons, M.; Gilks, B.; Yerushalmi, R.; Macpherson, E.; Carmichael, J.; Oza, A. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011, 12, 852−861. (16) Kaufman, B.; Shapira-Frommer, R.; Schmutzler, R. K.; Audeh, M. W.; Friedlander, M.; Balmana, J.; Mitchell, G.; Fried, G.; Stemmer, S. M.; Hubert, A.; Rosengarten, O.; Steiner, M.; Loman, N.; Bowen, K.; Fielding, A.; Domchek, S. M. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 2015, 33, 244−250. (17) Lynparza Approved in the European Union As First-in-Class Treatment for Advanced BRCA-Mutated Ovarian Cancer; AstraZeneca Global, 18 Dec 2014; http://astrazeneca.com. (18) LYNPARZA Approved by the US Food and Drug Administration for the Treatment of Advanced Ovarian Cancer in Patients with Germline BRCA Mutations; AstraZeneca Global, 19 Dec 2014; http:// astrazeneca.com. (19) Lynparza (Olaparib) Granted Breakthrough Therapy Designation by US FDA for Treatment of BRCA1/2 or ATM Gene Mutated Metastatic Castration Resistant Prostate Cancer; AstraZeneca, 28 Jan 2016; http://astrazeneca.com. (20) Miknyoczki, S.; Chang, H.; Grobelny, J.; Pritchard, S.; Worrell, C.; McGann, N.; Ator, M.; Husten, J.; Deibold, J.; Hudkins, R.; Zulli, A.; Parchment, R.; Ruggeri, B. The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to Temozolomide and irinotecan but does not potentiate myelotoxicity. Mol. Cancer Ther. 2007, 6, 2290−2302. (21) Lechaftois, M.; Dreano, E.; Palmier, B.; Margaill, I.; MarchandLeroux, C.; Bachelot-Loza, C.; Lerouet, D. Another ″string to the bow″ of PJ34, a potent poly(ADP-Ribose)polymerase inhibitor: an antiplatelet effect through P2Y12 antagonism? PLoS One 2014, 9, e110776. (22) Menear, K. A.; Hummersone, M. G.; Gomez, S.; Javaid, M. H.; Martin, N. M. B.; Kerrigan, F. Phthalazinone derivatives. WO 2009093032, 2009. (23) Awada, A.; Campone, M.; Varga, A.; Aftimos, P.; Frenel, J. S.; Bahleda, R.; Gombos, A.; Bourbouloux, E.; Soria, J. C. An open-label, dose-escalation study to evaluate the safety and pharmacokinetics of CEP-9722 (a PARP-1 and PARP-2 inhibitor) in combination with gemcitabine and cisplatin in patients with advanced solid tumors. AntiCancer Drugs 2016, 27, 342−348. (24) Bedikian, A. Y.; Papadopoulos, N. E.; Kim, K. B.; Hwu, W. J.; Homsi, J.; Glass, M. R.; Cain, S.; Rudewicz, P.; Vernillet, L.; Hwu, P. A phase IB trial of intravenous INO-1001 plus oral Temozolomide in subjects with unresectable stage-III or IV melanoma. Cancer Invest. 2009, 27, 756−763. (25) Thomas, H. D.; Calabrese, C. R.; Batey, M. A.; Canan, S.; Hostomsky, Z.; Kyle, S.; Maegley, K. A.; Newell, D. R.; Skalitzky, D.; Wang, L. Z.; Webber, S. E.; Curtin, N. J. Preclinical selection of a novel

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