Kinase and Histone Deacetylase Hybrid Inhibitors ... - ACS Publications

Perspective Cite This: J. Med. Chem. XXXX, XXX, XXX−XXX

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Kinase and Histone Deacetylase Hybrid Inhibitors for Cancer Therapy Yepeng Luan,† Jerry Li,‡ Jean A. Bernatchez,‡,§ and Rongshi Li*,†,∥ †

Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao 266071, Shandong Province, China Skaggs School of Pharmacy and Pharmaceutical Sciences, §Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States ∥ UNMC Center for Drug Discovery, Department of Pharmaceutical Sciences, College of Pharmacy, Fred and Pamela Buffett Cancer Center, and Center for Staphylococcal Research, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States J. Med. Chem. Downloaded from pubs.acs.org by UNIV OF GOTHENBURG on 01/27/19. For personal use only.

‡

ABSTRACT: Histone deacetylases (HDACs), encompassing at least 18 members, are promising targets for anticancer drug discovery and development. To date, five histone deacetylase inhibitors (HDACis) have been approved for cancer treatment, and numerous others are undergoing clinical trials. It has been well validated that an agent that can simultaneously and effectively inhibit two or more targets may offer greater therapeutic benefits over single-acting agents in preventing resistance to treatment and in potentiating synergistic effects. A prime example of a bifunctional agent is the hybrid HDAC inhibitor. In this perspective, the authors review the majority of reported kinase/HDAC hybrid inhibitors.

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INTRODUCTION Epigenetics is classically defined as the reversible changes in gene expression that do not result from changing DNA sequences. Epigenetics has been found to play an important role in the origin, development, and metastasis of cancer. Epigenetic writer, eraser, and reader enzymes, including histone deacetylase, DNA methyltransferase, and histone methyltransferase, have received increasing attention and are frequently studied as targets for drug discovery in cancer therapy. Of these epigenetics modifications, acetylation is the most common, playing important roles in the regulation of normal cellular processes such as cell differentiation, proliferation, angiogenesis, and apoptosis. Dysregulation of acetylation has been associated with diverse cellular events in cancer pathologies. Global hypoacetylation of H4 is one such common hallmark of tumors.1 The level of acetylation of histones and nonhistone proteins is governed by two antagonistic families of enzymes: histone deacetylases (HDACs) and histone acetyltransferases (HATs). HDACs are a family of ubiquitous enzymes found in bacteria, fungi, plants, and animals that are capable of removing an acetyl group from the ε-amino groups of lysine residues present within core histones and many nonhistone proteins. Consequently, the positive charge in the N-terminal region of histone cores increases and strengthens interactions with © XXXX American Chemical Society

negatively charged DNA while blocking access of transcriptional machinery to the DNA template, leading to gene silencing (Figure 1).2

Figure 1. Histone acetylation is regulated by HAT and HDAC.

The known HDACs are divided into four classes based on their sequence homology: class I HDACs include HDAC1, 2, 3, and 8; class II HDACs include classes IIa (HDAC4, 5, 7, and 9) and IIb (HDAC6 and 10); class III HDACs, known as sirtuins (sirt1−7); class IV HDAC (HDAC11).3 Silencing or inhibiting HDACs has been shown to affect cell cycle, cell growth, chromatin decondensation, cell differentiation, apoptosis, and angiogenesis in several cancer cell types.4 Thus, HDACs have emerged as important therapeutic targets in treating cancers. Accompanied by the extensive elucidation of mechanisms and functions of HDAC in tumorigenesis, the development of histone deacetylase inhibitors (HDACis) Received: February 5, 2018 Published: November 12, 2018 A

DOI: 10.1021/acs.jmedchem.8b00189 J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry

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this approach is frequently unable to provide effective and durable tumor suppression. Cancer cells can trigger other compensatory pathways for survival, and this accounts for much of the drug insensitivity and resistance. Several strategies may be applicable to solve this problem. One is a combination drug approach, but this strategy faces poor patient compliance, complex pharmacokinetics, and the challenge of drug−drug interactions that can severely affect the efficacy of one or more of the drugs administered.14 Another strategy is the development of therapeutic agents that incorporate several bioactive groups into a single molecule, which can produce compounds able to modulate multiple cellular pathways and which possess elevated efficacy compared to single-target agents. These can effectively overcome pharmacokinetic drawbacks and reduce development costs as well.15,16 Hybrid agents are thus powerful tools for anticancer drug discovery and in the authors’ view should have superior claims to be exploited.17 Treatment of tumor cells with HDACis can effectively induce a range of effects, including tumor cell apoptosis, cell cycle arrest, differentiation and senescence, modulation of immune responses, and blockade of angiogenesis.18 HDACis can thus be reasonably used in combination with other anticancer drugs, including cytotoxic drugs and small molecule inhibitors of defined targets.19 Co-administration of an HDACi with other anticancer drugs has already displayed promising augmented anticancer effects.19,20 Considering the direct tumoricidal activity of HDACis and their synergistic effect with other anticancer drugs, the hybrid HDACis, which combine two key fragments (i.e., the cap and ZBG groups) with an appropriate linker into a single molecule as a hybrid and that eventually act on two or more antitumor targets, have been validated and should offer the greatest advantage of the combined or additive effects of two drugs. Thus, the design of hybrid HDACis has attracted considerable attention. The main features of the published hybrid HDACis include: (i) an essential fragment of the inhibitor against another cancer target usually acting as the cap group of the hybrid HDACi, (ii) ZBG groups (the most commonly used are hydroxamic acid and benzamide), (iii) a linker that is the key factor affecting the activities for both targets, and (iv) the newly formed hybrids always showing potent and balanced inhibitory activities against HDACs and another cancer target. The fragments of the cap groups in reported hybrid HDACis are mainly from (i) kinase inhibitors, (ii) cytotoxic compounds,21 (iii) hormone receptor modulators,22 (iv) epigenetic modulators,23 (v) natural products,24 and (vi) other anticancer drugs or agents.25,26 Because the same strategy of hybrid HDACis applies to all six categories mentioned above, the general design of kinase/HDAC inhibitor hybrids is shown in Figure 3. In this Perspective, only those hybrid HDACis using the fragments from kinase inhibitors as cap groups are discussed while the hybrid

represents a powerful approach for cancer therapy. Apart from cancer, HDACs have also demonstrated value as targets for the treatment of diseases including Alzheimer’s,5,6 HIV-1 infection,7,8 and cardiovascular disease.9 In October 2006, the FDA approved the first HDACi, SAHA (vorinostat, 1 in Figure 2), used in treating rare

Figure 2. Five approved HDAC inhibitors.

cutaneous T-cell lymphoma. Currently, four HDAC inhibitors: 1, romidepsin (2), belinostat (3), and panobinostat (4) (Figure 2) have been approved by the FDA for the treatment of cancers including cutaneous T-cell lymphoma, peripheral Tcell lymphoma (PTCL), and multiple myeloma.10 The benzamide-based class I HDAC-selective inhibitor chidamide (5 in Figure 2) has recently been approved in China for the treatment of relapsed or refractory PTCL.10 Apart from these five approved treatments, there are several HDAC inhibitors at various stages of clinical trials against different cancers. In general, the canonical pharmacophore of the HDAC inhibitor is composed of three parts as shown in 1 in Figure 2: a cap structure that can interact with the rim at the entrance of the active pocket of HDACs, a zinc ion binding group (ZBG), and a linker responsible for the connection between the cap and the ZBG and for interaction with the hydrophobic tunnel of the active site.11 Of these three constitutive parts of the HDACi, the cap can adopt extensive structural variation, making it possible to design HDAC inhibitors with great variety of structures.

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HYBRID HDACIS Although HDACis have shown potent anticancer activities and five of them are in clinical use, side effects still exist, including thrombocytopenia, neutropenia, diarrhea, nausea, vomiting, fatigue, and cardiotoxicity.12−14 HDACis also tend to be less potent against solid tumors, which severely limits their employment in cancer therapy.13 To overcome these flaws, the development of new generation HDACis has thus far mainly focused on isoform-selective HDACis and multitarget HDACis which can also be termed as hybrid or bifunctional HDACis, with the latter gaining increasing attention. The mechanism of pathogenesis in cancer is known to be extremely complicated, with diverse enzymes, structural proteins, and transcription factors cooperating in the onset process. Although bioactive molecules that act on a single antitumor target are mostly used to suppress existing tumors,

Figure 3. Structural features of kinase/HDAC hybrid inhibitors. B



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Figure 4. Erlotinib-based hybrid HDAC inhibitors.

carbons being optimal. The structure of the linker could also affect the HDAC inhibitory activities. An ether linker is more potent than an amide linker, which is more potent than a thioether linker; a sulfone linker had the lowest potency. C-6 substituted compounds showed better inhibitory activity toward HDACs than those on C-7. Interestingly, substitution patterns of the quinazoline ring did not significantly affect HDAC inhibition. Among all these compounds, CUDC-101 (7 in Figure 4) was the most promising multitarget anticancer drug candidate. It is a first-in-class hybrid inhibitor of HDAC, EGFR, and HER2, with IC50 values of 4.4, 2.4, and 15.7 nM, respectively. 7 suppressed the proliferation of a panel of 11 human tumor cell types (including lung, liver, pancreas, and breast, with IC50 values lower than 1 μM) much better than 6 alone or a combination of 1 and 6. This was due to the ability of 7 to directly inhibit both EGFR and HER2 signaling and indirectly attenuate other survival signaling pathways, such as Akt, HER3, and MET.40 In addition to a potent antiproliferation effect, 7 could also prevent cancer cell migration and invasion that are lethal characteristics of cancer.41 In vivo, the antitumor efficacy of 7 was evaluated in a Hep-G2 liver cancer model at a daily dose of 120 mg/kg administered intravenously (iv). 7 induced 30% tumor regression and was more efficacious than 6 at its maximum tolerated dose (25 mg/kg, per os (po), daily) and 1 at a dose of 75 mg/kg (iv, daily). The phase I clinical trial study of the safety, pharmacokinetics, and antitumor activity of 7 was completed in 2010, where it displayed promising single-agent activity against advanced solid tumors and favorable pharmacodynamic profiles. The maximum tolerated dose was determined to be 275 mg/m2. The principal toxicities included transient reversible nausea (24%), fatigue (24%), dry skin (16%), serum creatinine elevation (12%), and serum AST elevation (12%).42 A subsequent phase I dose escalation study of 7 in combination with cisplatin administered intravenously and radiation therapy in patients with head and neck squamous cell cancer (HNSCC) was also completed in 2013. EGFR is overexpressed in up to 90% of HNSCC and HER2 is overexpressed in 20% to 40% of HSNCC; overexpression of both factors is associated with chemotherapy resistance. Twelve patients with intermediate or high-risk HNSCC enrolled. The initial dose of 7 for this clinical trial was 225 mg/m2, and the second dose was escalated to 275 mg/m2. 7 was administered by intravenous infusion over 1 h three times per week for 1 week, and cisplatin 100 mg/m2 was administered every 3 weeks. Results showed that the

HDACis derived from other anticancer agents (ii−vi) can be found elsewhere in the literature.21−26

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KINASE/HDAC HYBRID INHIBITORS Kinases are responsible for transferring phosphate groups from ATP to specific target molecules and have been among the most intensively pursued classes of drug targets, mainly for the treatment of cancers.27 More than 30 kinase inhibitor drugs have been approved.28,29 Among all kinase inhibitors, receptor tyrosine kinase (RTK) inhibitors have become important therapeutic agents in the fight against various cancers. Several RTK inhibitors have been approved by the FDA, and many others are in different phases of clinical trials. However, due to the heterogeneous and dynamic nature of tumors, the effectiveness of kinase inhibitors is often impaired by poor response rates and acquired drug resistance.30,31 To overcome these limitations, a number of strategies have been tested, including combination therapy and the development of multitarget inhibitors. HDACis were shown to synergize with RTK inhibitors by suppressing proliferation and inducing apoptosis in tumor cells, making tumor cells more susceptible to RTK inhibitor treatment and even overcoming RTK inhibitor resistance.32−37 Dual-acting hybrids that inhibit both HDAC and RTK have been widely reported.32−37 The structural features of such hybrids consist of a key fragment from the kinase inhibitors and a ZBG group from the HDACis with an appropriate linker as shown in Figure 3. The resulting kinase/HDAC hybrid inhibitors can simultaneously inhibit both HDACs and kinases.38 A. Erlotinib-Based Hybrid HDACis. Cai et al. designed and synthesized a series of compounds by integrating the hydroxamic acid group of an HDACi into the known epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) inhibitor erlotinib (6 in Figure 4). Both the quinazoline and phenyl-amino groups of 6 have key interactions in the ATP binding pocket with EGFR. However, the two methoxy−ethoxy groups at C-6 and C-7 do not bind directly to the receptor. This allows for structure modification at these positions without sacrificing the EGFR affinity. As a result, linkers with different spacers (ether, amide, sulfur ether, and sulfone) and lengths (three to five carbons) that terminated with a hydroxamic acid as a ZBG group were substituted on either C-6 or C-7 to inhibit HDACs. Several hybrid compounds showed potent inhibitory activity toward three enzymes: EGFR, HER2, and HDACs. 39 Structure−activity relationships (SAR) showed that the HDAC inhibitory activity correlated well with the linker length, with longer lengths being better and a length of six C



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Figure 5. Lapatinib-based hybrid HDAC inhibitors.

EGFR and HER2 was not dramatically affected following changes to side chain length. Regarding the aniline elements, size determined selectivity between EGRF and HER2. Among all compounds in this work, 11(Figure 5) displayed the best potency to EGFR, HER2, and HDAC1/6, with IC50 values of 0.12, 174.9, 0.72, and 3.2 nM, respectively. The antiproliferative activities of all synthetic compounds in this work were evaluated against A549 cells (EGFR overexpressed, k-Ras mutation) and BT-474 cells (HER2 overexpressed) with 1 and 8 as positive controls. Most of the compounds suppressed the growth of both cancer cell lines with IC50 values in the micromolar range, with almost all sixcarbon chain length compounds displaying better efficacies than the corresponding five-carbon chain length compounds. Moreover, 11 strongly inhibited the proliferation of A549 cells with an IC50 value of 0.63 μM, more effectively than 1 or 8 (IC50 = 2.57 and 1.74 μM for 1 and 8, respectively). However, 11 was less active against BT-474 cells (IC50 = 3.88 μM) due to its comparatively low potency toward HER2. In addition, 11 was able to block cellular EGFR and HER2 phosphorylation and induced histone H3 hyperacetylation and remarkable apoptosis in BT-474 cancer cells. C. Vandetanib-Based Hybrid HDACis. In Shi’s group, much effort was devoted to exploiting VEGFR/HDAC dual inhibitors, using 4-anilinoquinazoline as the template.47 In one study, a series of hybrids bearing N-phenylquinazolin-4-amine and hydroxamic acid moieties was designed by combining the fragments of vandetanib (12 in Figure 6) and 1 and were identified as dual VEGFR-2/HDAC inhibitors.48 Linker length was still a dominant factor that could also remarkably affect the inhibitory activity of HDACs. Compounds with a six-carbon linker were found to display the best activities. Furthermore, with respect to VEGFR-2 inhibition, all target compounds exhibited mild-to-moderate VEGFR-2 inhibitory activities compared to 12. The type and position of the substituent could dramatically influence VEGFR-2 inhibitory activity: introduction of 2, 4-Cl on the phenyl ring was preferred for the VEGFR-2 inhibition. Of all these novel hybrids, 13 (Figure 6)

combination of 7 and conventional chemoradiation was feasible and tolerated at biologically efficacious doses.43 B. Lapatinib-Based Hybrid HDACis. Mahboobi et al. reported a series of multifunctional inhibitors simultaneously targeted to EGFR/HER2/HDAC via combining the pharmacological activities of kinase and HDAC inhibitors. The structural element of either a hydroxamic acid or a benzamide derived from reported HDACis was transferred to the core structure of lapatinib (8 in Figure 5), a dual EGRF/HER2 small molecular inhibitor, to obtain new hybrid entities.44 The hybrids 9 and 10 (Figure 5), bearing an (E)-3-(aryl)-Nhydroxyacrylamide motif, exhibited the most potent inhibitory activities toward HeLa nuclear extract HDACs (IC50 values of 630 and 47 nM, respectively). This may be due to the structural similarities between their ZBG groups and 3; the substitution patterns of the N-hydroxyacrylamide moiety in 9, 10, and 3 are all meta to another substituent on the furan (9) or benzene ring (10 or 3). A transfer of this moiety from the meta to the para position drastically reduced the HDAC inhibitory potency. These two hybrid compounds also displayed very potent and specific inhibition of EGFR (IC50 = 25 and 18 nM, respectively) and HER2 (IC50 = 41 and 11 nM, respectively) kinase activities in biochemical assays. Hybrid 10 induced histone H3 hyperacetylation at 1 μM concentration, demonstrating that it is indeed a cellularly active, pharmacologically bifunctional compound. With regards to its cytotoxicity profile, hybrid 10 was broadly active, with IC50 values less than 1 μM, and was able to kill tumor cells completely at higher concentrations. One very recent study completed by Ding et al. reported a novel series of EGFR/HDAC multitarget inhibitors containing the 4-anilinoquinazoline skeleton of 8, a ZGB, and a 1,2,3triazole as the linker45 that is relatively resistant to metabolic degradation.46 Compounds with side chains of five or six carbons exhibited the best potency toward HDACs, and almost all compounds with a six-carbon chain displayed better potencies than counterparts having a five-carbon chain for the inhibition of HDAC1 and HDAC6. However, inhibition of D



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with the purpose of circumventing the poor efficacy of HDACis in solid tumors. 14 inhibited angiogenesis, a key physiological property required for growth and metastasis in solid tumors.50 The proposed binding mode (Figure 7A) indicated that the indazole moiety of 14 fits well into the interior pocket of VEGFR-2. The 2-aminopyrimidine moiety forms two hydrogen bonds with Cys917 in the hinge region, but the benzenesulfonamide is projected toward the solvent region. HDACis were designed based on the key fragment of 14 with ZBG being either hydroxamic acid or ortho-aminoanilide. Out of all compounds tested, the lead 15 (Figure 7B) with aminoanilide as ZBG showed the most balanced inhibitory activities against HDACs and VEGFR-1 to 3, with IC50 values of 4.6 μM, 37 nM, 22 nM, and 46 nM, respectively. Selectivity was achieved for 15 against HDAC1−3 over isoforms 6 and 8. Consistent with the authors’ predictions, 15 displayed potent antiproliferative activities not only to hematological tumors cell lines but also to solid tumor cell lines, with the most sensitive being HT-29 (IC50 = 1.07 μM). In an in vitro HUVEC tube formation assay, 15 inhibited tube formation as effectively as 14 at a concentration of 100 nM due to the former compound’s remarkable capability to inhibit VEGFRs. In addition, in an HT-29 xenograft model in nude mice, 15 effectively suppressed tumor growth at the dose of 50 mg/kg (po); inhibition was roughly half that of 14 (44%, po) at the same dose.50

Figure 6. A vandetanib-based hybrid HDAC inhibitor.

exhibited the most potent inhibitory activity against HDACs, with an IC50 value of 2.8 nM, and strong inhibitory effects against VEGFR-2, with an IC50 value of 84 nM. In vitro cell growth inhibition screening demonstrated that 13 also exhibited the greatest activity against the MCF-7 tumor cell line with an IC50 value of 1.2 μM (the IC50 values of 1 and 12 were 4.5 and 18.5 μM). D. Pazopanib-Based Hybrid HDACis. Pazopanib (14 in Figure 7B) is a potent RTK inhibitor acting on VEGFR-1 to 3 and can block tumor growth and inhibit angiogenesis. It was approved by the FDA in 2009 with indication for renal cell carcinoma. Combination therapies using 14 and diverse HDACis have been tested and have shown encouraging results,49 suggesting an attractive approach for the design of hybrid anticancer molecules. In work from Zhang’s lab, a series of novel hybrid HDACis was designed and synthesized based on the structure of 14

Figure 7. (A) The proposed binding mode of pazopanib in the ATP pocket of VEGFR-2 (PDB 3CJG). (B) Pazopanib-based hybrid HDAC inhibitor 15. E



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activity,70 the linker and ZBG for HDAC inhibition were incorporated here. Structural modification work verified the authors’ design concept that varying the linker at the C-7 position did not affect c-Met inhibition significantly. Different kinds of ZBG were investigated in this work, and it was found that the most potent was 17 (Figure 8), which inhibited c-Met kinase and HDAC1 with IC50 values of 0.71 and 38 nM, respectively. This hybrid also showed efficient antiproliferative activities against two tumor cell lines, EBC-1 (IC50 = 0.058 μM) and HCT-116 (IC50 = 1.3 μM), with greater potency than the reference compound 5 (IC50 = 2.9 and 7.8 μM) along with the parent compound 16(IC50 = 0.06 and >10 μM). The inhibition of phosphorylation of c-Met and its downstream signaling, as well as increased expression of Ac-H3 and p21 in EBC-1 cells were all evidence that 17 functioned well as a hybrid inhibitor. F. Abl/HDAC Hybrid Inhibitors. Imatinib (18 in Figure 9) is an approved Abl, PDGFR, and Kit inhibitor used in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and acute lymphocytic leukemia, which showed additive and synergistic effects when combined with HDACis.63,64 Mahboobi et al. reported the design and synthesis of a series of compounds that fused features of HDACis and 18 for the purpose of overcoming drug resistance.65 19 is one such example where a ZBG (orthoamino benzamide) moiety from HDACis is appended to the structure of 18. The HDAC inhibition profile of most hybrids remained conserved in biochemical and cellular assays, and their potency was comparable to that of 1. Inhibition of active Abl kinase was also conserved in most cases. Hybrid 19 exhibited high selectivity toward HDAC1 (class I, IC50 = 0.208 μM) over HDAC6 (class IIb, IC50 ≥ 32 μM). With regards to Abl kinase inhibition, hybrid 19 was the most active compound among all those synthesized with an IC50 value of 2 μM, comparable to that of 18 (IC50 = 1 μM). 19 could also inhibit AblT315I, a frequent mutation that causes resistance to 18, with an IC50 value of 1.1 μM. 19 also showed potent cellular inhibition of PDGFR (IC50 = 2.7 μM) and cytotoxicity toward EOL-1 cells (IC50 = 0.1 μM). G. PI3K/HDAC Hybrid Inhibitors. The phosphatidylinositol 3-kinases (PI3Ks) are a family of related intracellular signal transducer enzymes that are able to phosphorylate the 3hydroxyl group of the inositol ring of phosphatidylinositol. The PI3K family is divided into three classes according to sequence homology and substrate specificity. Dysregulation of PI3Ks and their downstream molecules plays an important role in cancer cell initiation, growth, proliferation, and survival.66 Thus, PI3Ks are frequently found to be in an activated state in many types of cancer.67 Several PI3K inhibitors are currently in clinical trials as monotherapy or in combination with other

E. c-Met/HDAC Hybrid Inhibitors. c-Met, which is encoded by the Met proto-oncogene, is an RTK that binds hepatocyte growth factor (HGF), resulting in activation of the receptor and recruitment of a number of adaptor proteins or effectors through downstream signaling pathways, including RAS/MAPK and PI3K/AKT. These latter pathways mediate several cellular properties including proliferation, survival, migration, mitogenesis, and angiogenesis.51,52 In contrast, aberrant c-Met activation, mutation, amplification, and translocation play important roles in cancer formation, progression, dissemination, and drug resistance.53,54 Moreover, increased levels of both c-Met and HGF are associated with poor clinical outcomes in cancer patients.55 c-Met kinase has thus received considerable attention as an intriguing target for cancer treatment,56 but, similar to other RTK inhibitors, the use of the c-Met inhibitor alone also causes problems of insufficiency in blocking tumor progression, and exhibits low efficacy and acquired resistance. c-Met inhibitors have emerged as an alternative option for hepatocellular cancer therapy,57 even as HDACis have been shown to exert a complementary effect when combined with other drugs to combat hepatocellular cancer.58−60 Using a successful RTK/HDAC hybrid inhibitor design, Lu et al. reported the first potent c-Met and HDAC hybrid inhibitor.61 A selective c-Met inhibitor62 (16 in Figure 8) was employed as

Figure 8. A selective c-Met-derived hybrid HDAC inhibitor.

the parental scaffold. Given that the SAR of 16 showed that the substituent at C-7 of the quinoline moiety extends into the solvent-exposed region of the protein and modification toward this position had no significant detrimental effect on inhibitory

Figure 9. Hybrid HDAC inhibitor based on the structure of imatinib. F



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drugs for the treatment of cancer, including apitolisib and pictilisib (20 and 21 in Figure 10).68,69 However, sole inhibition of the PI3K pathway is always problematic given the fact that other survival- and growth-related pathways are concurrently activated. Extensive evidence has implicated HDACis in the disruption of multiple pathways and HDACis are known to synergize with PI3K inhibitors.70−74 To overcome the limitations of targeting the PI3K pathway, Qian et al. first reported the rational design of a multitargeted compound, CUDC-907 (24 in Figure 12), as a drug candidate.75 An experiment was first performed to confirm that the combination of an HDACi (1) and a potent PI3K inhibitor (21) can exert a synergistic effect on growth inhibition of PC-3 prostate cancer cells. The combination index was significantly less than 1, which provided the rationale for the development of dual PI3K and HDAC inhibitors. On the basis of the result above, the authors incorporated a ZBG (hydroxamic acid) into the morpholinopyrimidine pharmacophore which is found frequently in reported PI3K inhibitors such as 20, 21, PI-103 (22 in Figure 10), and BKM-

Figure 11. Compound 21 binds the PI3K isoform p110γ active site with a critical H-bond (green dotted line) formed between the oxygen atom of the morpholine moiety and the hydrogen of the Val882 residue (PDB 3DBS).

a promising therapeutic index in MYC-dependent cancers77 such as B-cell lymphoma.78 In an in vivo animal model of Daudi non-Hodgkin’s lymphoma, tumor growth was inhibited by oral administration of 24 in a dose-dependent manner. Tumor stasis was observed at 100 mg/kg without obvious toxicity. Notably, 24 (100 mg/kg) achieved better efficacy than 1 or 21 given at their maximal tolerated doses of 120 and 150 mg/kg, respectively, and a combination of 1 and 21 (doses of 60 and 75 mg/kg, respectively). The study of in vivo antitumor activity showed that 24 inhibited HDACs as demonstrated by the accumulation of acetylated histone H3 and PI3K resulting from a decrease in p-AKT. In addition, mouse pharmacokinetic studies showed that 24 had an oral bioavailability approximately 2-fold higher than 1. In a phase I study to evaluate the safety, tolerability, and preliminary activity of 24 in patients with relapsed or refractory lymphoma or multiple myeloma, five of 37 (14%) evaluable patients achieved an objective response (two complete responses and three partial responses).69 24 is currently undergoing a phase II clinical trial in patients with lymphoma and in patients with advanced thyroid cancer. However, acquired resistance remains a challenge for its therapeutic use. In this regard, the ATP-binding cassette (ABC) drug transporter ABCG2 is one of the central players in the development of resistance to 24; combination therapy with an ABCG2 inhibitor should be a good choice for improving the pharmacokinetics and efficacy of 24.79 Inspired by the discovery of 24, Chen et al. designed and synthesized a group of novel PI3K/HDAC hybrid inhibitors. Considering that purines are employed as the core scaffold in many PI3Ks inhibitors,80,81 and the morpholine group is imperative for activity, the authors designed new hybrids by replacing the morpholinopyrimidine moiety in 24 with a morpholinopurine scaffold.82 All obtained compounds showed strong inhibitory activity toward HDAC1, with the substituent at the C-2 position of the morpholinopurine having a profound effect on PI3K inhibition. A phenyl group at this position was found to be detrimental, while 25 and 26 (Figure 12), which have a pyrimidine at the C-2 position of the morpholinopurine moiety, displayed the expected dual PI3Kα and HDAC1 inhibitory activities. The IC50 values for 25 against HDAC1 and PI3Kα were 1.14 and 28.06 nM, respectively. 26 showed

Figure 10. Structures of PI3K inhibitors containing a morpholine group.

120 (23 in Figure 10). It is noteworthy that the morpholine ring has proved to be essential for the inhibitory activity toward PI3K, due to the fact that a key hydrogen bond is formed between the oxygen atom of the morpholine and the hinge region of the ATP binding domain, as exemplified by the binding modes of 21 (Figure 11).76 24, a first-in-class, orally active, multitargeted inhibitor was obtained via this aforementioned structural modification. First, 24 is a potent inhibitor of class I PI3K kinases with IC50 values of 19, 54, and 39 nM for PI3Kα, PI3Kβ, and PI3Kδ, respectively. Second, 24 is also a potent pan-HDACi against classes I and II HDACs. Its potency against class I HDACs was like that of 4 and greater than that of 1, as shown in Table 1. Through its integrated HDAC inhibitory activity, 24 could durably inhibit the activation of the PI3K-AKT-mTOR pathway and compensatory signaling molecules, including RAF, MEK, MAPK, and STAT-3, as well as upstream RTKs in Western blot analysis with a concentration of 100 nM. In vitro, 24 induced apoptosis and G2−M cell-cycle arrest in HCT-116 cancer cells by activation of caspase-3 and -7. 24 also displayed G



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Table 1. Inhibition of the Enzymatic Activities of HDACs 1 through 11 by 24 and Reference Compounds 1 and 471 HDAC isoforms (IC50 in nM) 1 1 4 24

42.5 1.4 1.7

2 156 6.8 5.0

3 33.1 1.5 1.8

4 113 26.7 191

5 a

NA 195.6 406

6

7

8

9

10

11

NA 123.8 674

21.6 8.2 27

NA 1864 426

NA 922.2 554

68.4 2.1 2.8

51.3 1.6 5.4

a

NA: not active.

Figure 12. Structures of PI3K/HDAC hybrid inhibitors.

excellent HDAC inhibitory activities.86−88 In all of the target compounds synthesized, 28 (Figure 13) was shown to be a potent and dual inhibitor of c-Src kinase and HDAC1 (Ki = 138 and 0.26 nM, respectively). At the cellular level, 28 could potently inhibit the proliferation of SK-BR-3 cells with GI50 value of 0.2 μM, better than treatment with 1 (GI50 = 1.2 μM), 27 (GI50 = 4.8 μM), and their 1:1 combination (GI50 = 0.8 μM). In the following NCI-60 panel screening, 28 still displayed high efficacy against all cancer cell lines including MCF-7 (GI50 = 0.35 μM) and KM12 (GI50 = 0.47 μM), which were less susceptible to single treatment with 1 (GI50 = 2.19/ 1.88 μM), or dasatinib, a dual Abl/Src inhibitor (GI50 = 8.32/ 7.44 μM). All these results fully validated 28 as a successful example of a hybrid Src/HDAC inhibitor. I. Janus Kinase/HDAC Hybrid Inhibitors. The Janus kinase (JAK) proteins, a family of intracellular, nonreceptor tyrosine kinases including JAK1, JAK2, JAK3, and TYK2, are involved in cell growth, survival, development, and differentiation of a variety of cells.89 Genetic studies have identified a somatic JAK2V617F mutation that activates the JAK−STAT signaling pathway in most patients with myeloproliferative neoplasms (MPNs, and have resulted in a molecular classification and an improved understanding of pathogenesis.90 Following the discovery of this mutation, JAK inhibitors have been rapidly developed for the treatment of MPNs. On the other hand, some HDACis have been shown to be effective against MPNs both as a single agent and in conjunction with JAK2 inhibitors.91 Therefore, dual inhibition of JAKs and HDACs in a single molecule represent a compelling new anticancer strategy. Inspired by the concept of multitarget HDACis and with the aim of improving the therapeutic effectiveness for MPNs, Dymock’s group designed novel hybrid HDACis by merging the structures of a selective JAK2 inhibitor, pacritinib (29 in Figure 14), and 1 to create single molecules with both JAK2 and HDAC inhibitory activities.92 Because many potent HDACis possess a macrocycle structure, such as 2, it was postulated that the macrocyclic ring of 29 could be also a desirable cap group for HDACi design. Furthermore, it was believed that isoform selectivity could be achieved by those HDACis having a large cap group.93 On the other hand, it is known that the pyrolidine ring on the side chain of 29 is

lower and balanced IC50 values for HDAC1 and PI3Kα, 1.04 and 1.33 nM, respectively, compared to 1.7 and 19 nM for 24, which was the positive control. 26 also exhibited good in vivo antiproliferative activity in a MV4−11 xenograft NOD/SCID mouse model at a dose of 10 mg/kg (iv); the tumor mass inhibition rate was 45.1%. In contrast, compound 1 (acting as a positive control) had no inhibitory activity at 50 mg/kg intraperitoneal (ip) dosing in this model. H. c-Src/HDAC Hybrid Inhibitors. Proto-oncogene tyrosine−protein kinase Src (c-Src) plays a key role in many aspects of cell physiology, regulating diverse cellular processes including division, motility, adhesion, angiogenesis, and survival. c-Src is frequently overexpressed in cancers. The extent of overexpression of c-Src correlates with malignant potential.83 To search for drugs that would affect c-Src inhibition, Soellner et al. evaluated a small library of targeted inhibitors and identified the HDACi 4 as highly synergistic with c-Src inhibition. This result was attributed to the ability of HDACis to down-regulate c-Src levels via repression of SRC transcription.84 On the basis of the effects that occur between c-Src and HDACis, a small series of chimeric inhibitors that inhibited both c-Src kinase and HDACs was designed and synthesized.85 In this work, the PP2-alkyne (27 in Figure 13), a selective cSrc kinase inhibitor with an alkyne group in its structure, was used as the template, and the ZBG was appended by a triazole group formed by “click chemistry.” In fact, several published HDACis containing a triazole as cap or linker have displayed

Figure 13. A c-Src/HDAC hybrid inhibitor. H



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Figure 14. JAK2/HDAC hybrid inhibitors.

32 showed broad antiproliferative activity toward different solid and hematological tumor cell lines such as MDA-MB231, MCF7, and Jurkat, with IC50 values of 0.79, 0.84, 0.47 μM, respectively. The broad cellular antiproliferative potency of 32 is also supported by the JAK-STAT and HDAC pathway blockade in hematological cell lines. Of note, another hybrid, 33 (Figure 14), a methylated analogue of 32, had an even more selective inhibitory profile toward HDAC6 (IC50 = 1 nM) and HDAC1 (IC50 = 6 nM) over other HDACs. Because there are still no published crystal structures of 31 in complex with JAK kinases, this work not only provides two new leads 32 and 33 for simultaneous inhibition of the JAK2 and HDAC pathways achieved by a single molecule but also paves a way for the design of novel JAK2/HDAC hybrid inhibitors with stronger activity.

located in a solvent exposed region lacking any interaction with JAK2.92 Thus, the authors chose to insert the HDAC binding group here to retain the inhibitory activity toward JAK2. Although the structure of the side chain was diversified, significant inhibition of JAK2 was retained by all synthesized compounds. The result was consistent with the authors’ postulate that for HDAC inhibition, the bulk and length of the side chain had a profound effect on activity. 30 (Figure 14), with a long-chain aliphatic hydroxamic acid, had the best HDAC6 inhibitory activity of this series, with an IC50 of 2.1 nM and good selectivity over other HDAC isoforms, which can be explained by the larger lip of the substrate binding pocket of HDAC6 in our view. A good balance was also achieved for inhibition of JAK2, with the IC50 value reaching 1.4 nM. The induction of Ac-H3 and decreased expression of STAT3 in intracellular assays further showed that 30 was a bifunctional inhibitor. In an extended work by the same group, a novel series of dual JAK and HDACis was designed and synthesized based on the core features of ruxolitinib (31 in Figure 14), a marketed JAK1/2 inhibitor, and 1.94 In their design, the pyrrolpyrimidine motif that mediates a critical donor−acceptor hydrogen-bonding interaction between 31 and the hinge region of JAK1/2 kinases was retained, and flexible alkyl chains were appended to the pyrazole moiety of 31. The ZBG was located at the end point, occupying a tolerated position near the solvent region, and various alkyl chains were also evaluated. The compound with a six-carbon linker exhibited the most potent inhibitory activities toward both HDACs and JAK2. Hybrid 32 (Figure 14) inhibits HDAC1, HDAC6, and JAK2 with IC50 values in the nanomolar range (6.9, 1.4, and 75 nM, respectively), while the IC50 of 31 as a control was 56 pM against JAK2, which demonstrated that the existence of a long chain and the ZBG somehow hindered the interaction between the hybrids and JAK2, but no inhibition of HDACs 1 or 6 was observed for 31. In addition, 32 was also a potent inhibitor toward HDAC2, HDAC3, and HDAC10, with IC50 values of 5.8, 3.9, and 19 nM, respectively. 32 was selective for the JAK family against a panel of 97 other kinases including FLT3, which can be inhibited by 31.

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CONCLUSION AND PERSPECTIVE It is not our intention to cover all kinase/HDAC hybrid inhibitors in the public domain. The nine case studies discussed here vide supra illustrate how hybrid HDACis are designed. There are always potential risks when two molecules are combined into a single agent because the resulting hybrid compound may not be able to exhibit desirable biological and/ or pharmacological functions due to steric or repulsive interactions with the targets. To design effective kinase/ HDAC hybrid inhibitors, certain general procedures include (i) discovery of multitarget synergy for anticancer agents, (ii) identification of the key fragments (or scaffolds) from both kinase inhibitors and HDACis, (iii) identification of an appropriate spacer to link the fragments at positions where substitution does not affect the activity,(iv) SAR studies of derivatives and iterative optimization, and (v) selection of lead compounds for further development into a therapeutic agent. Synergy of multitarget agents can be discovered by counterscreening either kinase inhibitors or HDACis against each other’s target enzymes or through combination therapy. The key fragments of kinase inhibitors that act as a cap for hybrid agents must possess functional groups or scaffolds that can interact with kinases in the hinge region through hydrogen bonding, usually in ATP binding pockets. Disruption of such I



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interactions is detrimental and can result in a loss of affinity. The key fragments for HDACis are ZBG hydroxamic acid and ortho-amino benzamide functional groups. Fortunately, HDACs can tolerate a variety of structures as a cap. Bulky and flat kinase inhibitor cap structures can be accommodated by HDACs. An appropriate spacer, usually a five- or six-carbon chain, can link the cap and ZBG fragments. The points of substitution for kinase inhibitor fragments should be those that least affect kinase inhibition after substitution (usually in solvent accessible regions). Iterative SAR optimization can help identify critical structural elements in lead compounds to further develop these molecules into therapeutic agents. As one of the most important tumor-promoting enzymes in the area of epigenetics, HDACs are responsible for deacetylation of acetyllysine (KAc) residues in histones and nonhistone substrates. They have emerged as attractive targets for the development of novel anticancer agents, some of which have been used clinically. Even so, old-generation HDACis are usually isoform nonselective or partially selective, often accompanied by unwanted side effects. In addition to these drawbacks, most old-generation HDACis show limited efficacy against solid tumors, which seriously limits their application for the treatment of a broader spectrum of cancers. To overcome these flaws, the development of new generations of HDACis can be divided into two areas, the first of which is the isoform selective HDACis, while the second is hybrid HDACis. The poor pharmacokinetic profile of the hybrid HDACis due to inactivation by glucuronidation of hydroxamic acid and ortho-amino benzamide ZBG is a problem to be addressed. Fortunately, an alternative ZBG (hydrazide) with potent activity and improved properties has been reported,95 which can be utilized for the design of novel hybrid HDACis in the future. So far, the number of hybrid HDACis that have entered clinical trials is still limited. Even so, two hybrid HDACis, 7 and 24,42,43,96 are currently in clinical trials, which provides validation for this design strategy. It is anticipated that hybrid HDACis will attract increasing attention, and their development is likely to flourish soon.

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Jerry Li (Pharm.D.) received his Bachelor of Arts degree in molecular cell biology at the University of California, Berkeley, and his Doctor of Pharmacy degree at the University of Michigan College of Pharmacy. He is currently completing a postdoctoral fellowship in clinical pharmacology at the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego, and Pfizer Global Research and Development, La Jolla Laboratories. Jean A. Bernatchez (Ph.D.) completed his B.Sc. (First-Class Honors) in Biochemistry at McGill University in Montreal, Quebec, Canada, in 2008. He then pursued Ph.D. studies at McGill in Biochemistry as part of the Chemical Biology Interdepartmental Graduate Program and graduated in 2015. Currently, Dr. Bernatchez is a Postdoctoral Scholar at the Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego. His current research focus is on the development and use of phenotypic, cell-based high-throughput screening assays for the discovery of novel anticancer, antiviral and antiparasitic agents. Rongshi Li is a Professor of Chemistry and Medicinal Chemistry at the University of Nebraska Medical Center (UNMC). After 14 years in industry, advancing from Scientist to Senior Vice President, Dr. Li moved to Moffitt Cancer Center in Tampa, Florida. In 2013, he was recruited to UNMC, where he has received the Distinguished Scientist Award (2016) and New Invention Awards (2014, 2016, 2018). Dr. Li has over 200 scientific contributions including peerreviewed articles, patents, reviews/Perspectives, book and book chapters, editorial, and published scientific presentations. Dr. Li has delivered more than one hundred lectures as a keynote or invited speaker at numerous universities and research institutions and at national and international symposia, and he has been a Guest Editor for Medicinal Research Reviews.

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ACKNOWLEDGMENTS We gratefully acknowledge the financial support from the National Science Foundation for Young Scientists of China to Y. L. (NSFC no. 81602947). This work is partially supported by startup funds to R.L. provided by the University of Nebraska Medical Center.

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AUTHOR INFORMATION

Corresponding Author

ABBREVIATIONS USED ABC, ATP-binding cassette; ABCG2, ATP-binding cassette subfamily G member 2; AML, acute myeloid leukemia; ATP, adenosine triphosphate; FDA, U.S. Food and Drug Administration; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDACi, histone deacetylase inhibitor; JAK, Janus kinase; MPN, myeloproliferative neoplasm; PI3K, phosphatidylinositol 3-kinase; PTCL, peripheral T-cell lymphoma; RTK, receptor tyrosine kinase; SAHA, suberoylanilide hydroxamic acid; SAR, structure−activity relationship; VEGFR, vascular endothelial growth factor receptor; ZBG, zinc ion binding group

*Phone: (402)559-6609. E-mail: [email protected]. ORCID

Rongshi Li: 0000-0002-1774-7827 Author Contributions

Y.L., J.L., and J.A.B. contributed equally. All authors wrote and revised the manuscript. Notes

The authors declare no competing financial interest. Biographies Yepeng Luan (Ph.D.) received his doctoral degree in 2010 from the Department of Medicinal Chemistry, School of Pharmacy, Shandong University, China. During this period, he did a year of research as a visiting student at the Department of Pharmaceutics at the University of Kansas. His postdoctoral training was at Ocean University of China (2010−2012) and the University of Georgia (2012−2015). Dr. Luan is a lecturer in the Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, China. His research focuses on the design, synthesis, and activity evaluation of novel isoform-selective HDAC inhibitors and hybrid HDAC inhibitors. He is also interested in designing novel antagonists against other epigenetic targets, including HAT and protein arginine methyltransferases.

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