Inhibitors of Mutant Isocitrate Dehydrogenases 1 ... - ACS Publications

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Inhibitors of Mutant Isocitrate Dehydrogenases 1 and 2 (mIDH1/2): An Update and Perspective Tianfang Ma,†,‡,⊥ Fangxia Zou,†,‡,⊥ Stefan Pusch,§,∥,⊥ Yungen Xu,‡ Andreas von Deimling,§,∥ and Xiaoming Zha*,†

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Department of Pharmaceutical Engineering and Department of Biochemical Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China ‡ Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, P. R. China § German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), INF 280, Heidelberg D-69120, Germany ∥ Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-Universität Heidelberg, INF 224, Heidelberg D-69120, Germany S Supporting Information *

ABSTRACT: Isocitrate dehydrogenases 1 and 2 (IDH1/2) are homodimeric enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid cycle. However, mutant IDH1/2 (mIDH1/2) reduces α-KG to the oncometabolite 2-hydroxyglutarate (2-HG). High levels of 2-HG competitively inhibit the α-KGdependent dioxygenases involved in histone and DNA demethylation, thereby impairing normal cellular differentiation and promoting tumor development. Thus, small molecules that inhibit these mutant enzymes may be therapeutically beneficial. Recently, an increasing number of mIDH1/2 inhibitors have been reported. In this review, we summarize the molecular basis of mIDH1/2 and the activity, binding modes, and progress in clinical application of mIDH1/2 inhibitors. We note important future research directions for mIDH1/2 inhibitors and discuss potential therapeutic strategies for the development of mIDH1/2 inhibitors to treat IDH1/2 mutated tumors. inhibitors.7 Furthermore, future research directions involving mIDH1/2 inhibitors are also discussed to provide a reference for potential therapeutic strategies for the treatment of IDH-mutant tumors.

1. INTRODUCTION Isocitrate dehydrogenases (IDHs), which include three subtypes (IDH1, IDH2, and IDH3), catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and are involved in multiple metabolic processes.1 IDH2 and IDH3 are both located in the mitochondria, whereas IDH1 is located in the cytosol and peroxisomes.2 Somatic mutations in IDH1/2 have been found in several human cancers including glioma, acute myeloid leukemia (AML), intrahepatic cholangiocarcinoma, and chondrosarcoma.3 The mutant IDHs lose their normal enzymatic activities and instead gain a neomorphic activity and produce the “oncometabolite” 2-hydroxyglutarate (2-HG).4 High levels of 2-HG competitively inhibit the α-KG-dependent dioxygenases involved in histone and DNA demethylation, thereby impairing normal cellular differentiation and promoting tumor development (Figure 1).5 To date, several inhibitors of mutant IDH1/2 (mIDH1/2) have entered clinical trials, and the mIDH2 inhibitor AG-221 (also known as enasidenib; see section 3.2.1 for its details) has been launched for the treatment of AML. These molecules have shown encouraging results in patients with IDH-mutant hematologic and solid tumors.6 Unlike other reviews, this article focuses on the molecular basis of mIDH1/2 and the clinical progress of reported mIDH1/2 © 2018 American Chemical Society

2. MUTANT IDH1/2 IN TUMORIGENESIS Mutations in IDH1/2 predominantly consist of a change in a single residue in the active site. The most common mutations are to arginine at position 132 in IDH1 and at position 140 or 172 in IDH2.8 Other missense mutations lead to a wide range of substitutions, including polar (C, T, Q, H, K, S) and some nonpolar (M, V, W) amino acids, in which R132H accounts for more than 93% of IDH1 variants while the R140Q mutant is predominant in AML.9,10 Studies have demonstrated that more than 70% of low-grade gliomas and up to 20% of secondary glioblastoma multiforms are related to IDH1 mutations.11,12 Moreover, IDH1 mutations also occur in about 10% of AML cases, 10% of cholangiocarcinomas and other indications.11−13 However, mutant IDH2 is only found in about 4% of gliomas and 10% Received: January 30, 2018 Published: May 31, 2018 8981

DOI: 10.1021/acs.jmedchem.8b00159 J. Med. Chem. 2018, 61, 8981−9003

Journal of Medicinal Chemistry

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Figure 1. Functions of normal and mutated IDH.

Figure 2. Chemical structures of compounds 1−3.


normally produced in low amounts by errors in catalysis (50 μM, and >50 μM against IDH1 R132H, IDH1 R132C, WT-IDH1, and WT-IDH2, respectively, 8988



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IC50 values of 220 nM against IDH1 R132H and 150 nM against IDH1 R132C, was identified as a lead compound for the development of novel mIDH1 inhibitors such as IDH 662 (28) (IC50 = 38 nM) and IDH 889 (29) (IC50 = 20 nM).74 While 28 showed relatively strong cytotoxicity toward WT-IDH1 (IC50 = 1.03 μM), 29 exhibited excellent selectivity over WT-IDH1.74,75 Moreover, 29 also exhibited better brain permeability and deserves further optimization for the treatment of patients with IDH1-mutated brain tumors.74 Currently, 29 is in the preclinical stage of development as a potential drug for the treatment of cancers with IDH1 mutations. Two other analogs, 30 and 31, showed potent inhibitory effects of the IDH1 R132H homodimer in fluorescence-based biochemical assays (IC50 < 100 nM).73,74 IDH 305 (32, Figure 12), obtained by the optimization of 29 for potency and pharmacokinetic (PK) properties, is a highly potent allosteric inhibitor that selectively inhibits mutant IDH1 and induces cell differentiation in vivo and ex vivo.76,77 It showed strong inhibitory potency toward IDH1 R132H (IC50 = 0.018 μM) and exhibited better brain penetration than 29.77 A nonrandomized, open-label phase II clinical trial of 32 was recently begun in patients with IDH1-mutated low-grade gliomas or grade II or III gliomas for the treatment of solid tumors, myeloid leukemia, and neurological cancer (NCT02987010 and NCT02977689).77 The preliminary results demonstrated an objective response rate ranging from 31% to 40% with durable responses (>1 year) observed.78 As shown in the crystal complex of IDH1 R132H (PDB code 5SUN), IDH 146 (33, Figure 13) binds in an allosteric pocket of mIDH1, which accounts for its inhibitory activities against IDH1 R132H (IC50 = 590 nM) and IDH1 R132C (IC50 = 50 nM).80 1-(2-(Ethylamino)pyrimidin-4-yl)pyrrolidin-2-one Scaffold. A series of 1-(2-(ethylamino)pyrimidin-4-yl)pyrrolidin-2-onebased mIDH1 inhibitors was patented by Novartis scientists in 2014 for the treatment of diseases associated with IDH1 mutations.79 More than 100 compounds were reported, and most of them exhibited potential IDH1 R132H and IDH1 R132C inhibition, as determined by enzyme-linked fluorescence assay.79 The structures of compounds 34−38, which have highly potent inhibitory activities (IC50 < 100 nM), are listed in Figure 14.

Figure 19. Chemical structure of compound 62.

3.1.9. Forma Therapeutics Compounds. Forma Therapeutics scientists reported three patent applications claiming quinolonebased mIDH1 inhibitors in 2016.80−82 Compounds 39−47 (Figure 15) are selected candidates reported in the three patent applications that are claimed to show strong inhibitory activities (IC50 < 10 nM) against IDH1 R132H and IDH1 R132C in enzyme-linked fluorescence assays.80−82 The cellular activities of these compounds were also tested via the detection of D-2-HG levels in human HCT-116 cells overexpressing mIDH1.80−82 Currently, Forma is developing FT-2102 (structure not yet disclosed) as an oral formulation for the treatment of AML and myelodysplastic syndrome in an open-label, multicenter phase I trial (NCT02719574) aiming to evaluate its safety, PK, and pharmacodynamic (PD) profiles alone or in combination with azacitidine. Approximately 48 patients will be enrolled in the dose-escalation portion of this study in one or more schedules, followed by approximately 14 patients in the expansion cohorts. 3.1.10. Daiichi Sankyo Compounds. DS-1001 (also known as DS-1001b, structure not determined) is a potent oral mIDH1 inhibitor discovered by Daiichi Sankyo. DS-1001 has recently entered an open-label, multicenter phase I trial to assess its safety, tolerability, pharmacodynamics, and antitumor activity in patients with gliomas harboring IDH1 R132 mutations in Japan.83 The study also aims to determine the maximum tolerated dose (MTD) and/or recommended phase II dose of DS-1001 (NCT03030066).83 3.1.11. Eli Lilly Compounds. 7-Phenylethylamino-4Hpyrimido[4,5-d][1,3]oxazin-2-one Scaffold. In 2017, Lilly 8989



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reported a series of 7-phenylethylamino-4H-pyrimido[4,5-d][1,3]oxazin-2-one compounds as mutant IDH1 covalent inhibitors, in which N-acryloyl azetidines could present Michael acceptors to nucleophilic residues in mutant IDH1 and enable these compounds to efficiently and quickly react with the protein.84 Among them, compound 48 (Figure 16) effectively inhibited IDH1 R132H and IDH1 R132C mutants (IC50 = 29.1 nM and 26.6 nM, respectively) and exhibited good selectivity against WT-IDH1, WT-IDH2, IDH2 R140Q, and IDH2 R172K with IC50 values of 3800, 10700, 41800, and 1670 nM, respectively.85 Meanwhile, in vivo studies suggested that 48 dose-dependently inhibited 2-HG production in athymic nude mice bearing IDH1 R132C-positive HT-1080 and IDH1 R132H-positive human glioblastoma TB08 xenografts.85 Other representative compounds (49−53) (IC50 < 100 nM) from the patent (WO 2017019429) are presented in Figure 16. Novel 3-Pyrimidin-4-yl-oxazolidin-2-one Scaffold. Subsequently, another series of potent mIDH1 inhibitors with a novel 3-pyrimidin-4-yl-oxazolidin-2-one scaffold were patented by Lilly scientists in 2017 and also includes the N-acryloyl azetidine element designed for covalent inhibiton.84 Most compounds in the patent application were claimed to exhibit potent inhibition of IDH1 R132H and IDH1 R132C (IC50 < 100 nM), and compound 54 (Figure 17) showed strong inhibitory activity against IDH1 R132H and R132C with IC50 values of 0.011 μM and 0.00889 μM, respectively, and good selectivity against WT-IDH1.86 The structures of the representative compounds 55−57 are presented in Figure 17. 3.1.12. Merck Compounds. Recently, a series of novel tricyclic compounds that act as mIDH1 inhibitors were discovered by Merck & Co. for the treatment of cancers with IDH1 mutations. Compound 58 (Figure 18) strongly inhibited IDH1 R132H

Figure 21. Chemical structures of compounds 67 and 68.


(IC50 = 3.5 nM) in Kinase-Glo luminescent assays.87 The patent application also claimed the potent mIDH1 inhibitors 59−61 with significant inhibitory activities against mIDH1 (IC50 < 10 nM) (Figure 18).87 8990



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3.1.13. Zhejiang University of Technology (ZJUT) and Shanghai Institute of Materia Medica (SIMM) Compounds. Researchers from Zhejiang University of Technology (ZJUT) and Shanghai Institute Materia Medica (SIMM) collaborated to discover a series of double aryl maleimide compounds that act as novel mIDH1 inhibitors for treating glial tumors, acute myelogenous leukemia, and other malignant tumors mediated by mutant IDH1. The representative compound 62 (Figure 19) exhibited strong inhibition of IDH1 R132H and IDH1 R132C with IC50 values of 0.09 and 0.38 μM, respectively, as well as high selectivity against WT-IDH1 in fluorescence-based assays.88 In addition, at 5 and 20 μM, it significantly suppressed 2-HG production in a concentration-dependent manner in human glioblastoma U-87 MG cells overexpressing IDH1 R132H.88 3.1.14. Shanghai HaiHe Pharmaceutical Compounds. Recently Shanghai HaiHe Pharmaceutical Co. collaborated with SIMM and reported a series of novel mIDH1 inhibitors, most of which exhibited significant inhibitory potency against IDH1 132H (IC50 < 100 nM).89 Among the compounds 63−66 disclosed by this group and shown in Figure 20, compound 63


reduced 2-HG levels in human fibrosarcoma HT-1080 cells with an IC50 value of 10 nM.89 On the basis of AG-120 discovered by Agios, the Wan group from Shanghai HaiHe Pharmaceutical developed another class of conformationally restricted indane analogs as IDH1 inhibitors.90 The installation of a quaternary center at the α-position of the amide would prevent epimerization and potentially slow down amide hydrolysis. Compounds 67 and 68 (Figure 21) strongly inhibited IDH1 R132H with IC50 values of 45 nM and 49 nM, 8991



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respectively, and showed significant selectivity against WT-IDH1 and IDH2 140Q.90,91 Notably, both 67 and 68 exhibit favorable PK properties in mice.90,91 3.1.15. Chia Tai Tianqing Compounds. Jiangsu Chia Tai Tianqing Pharmaceutical and collaborators simultaneously disclosed two patents for novel mIDH1 inhibitors with sultam (form I) or aziridinesulfonamide scaffolds (form II). Compound 69 (Figure 22) from one patent application, which has a sultam scaffold, displayed potential inhibition against IDH1 132H in human fibrosarcoma HT1080 cells and against IDH1 132C in human glioblastoma U-87 cells (IC50 < 20 nM for both) in cellular 2-HG assays.92 Compound 70 (Figure 22), which has an aziridinesulfonamide scaffold, was reported in the other patent application to inhibit IDH1 R132H with an IC50 of less than 20 nM in NADPH depletion assays.93 Both 69 and 70 exhibited good PK properties for the treatment of cancers with IDH1 mutations.92,93 3.1.16. UNC Compounds. The University of North Carolina at Chapel Hill (UNC), in collaboration with the U.S. Department of Health and Human Services, developed a series of thiazole derivatives as mIDH1 inhibitors, among which the representative compounds 71−73 (Figure 23) exhibited significant inhibitory potency against IDH1 R132H and IDH1 R132C (IC50 < 0.3 μM) in enzymatic assays.94 3.1.17. Other mIDH1 Inhibitors. HMS-101. Using virtual screening, Chaturvedi et al. identified an mIDH1 inhibitor (HMS-101, 74, Figure 24) that efficiently blocked the colony formation of leukemia cells from patients with IDH1-mutated AML and significantly decreased 2-HG levels in vitro but did not affect normal CD34+ marrow cells.95 FX-03. Docking-based screening of mIDH1’s allosteric site led to the identificaiton of FX-03 (75, Figure 24) as a mIDH1 inhibitor with IC50 values of 55.50 μM and 65.38 μM against IDH1 R132H and IDH1 R132C, respectively, in HEK293T cells.14 Interestingly, 75 displayed very weak cytotoxicity against HEK293T cells expressing WT-IDH1 at 50 μM.20


Clomifene. Drug repurposing may be an effective route for the rapid development of new drugs. Clomifene (76, Figure 24), a selective estrogen receptor modulator for the treatment of female infertility, was discovered to be an mIDH1 inhibitor by structurebased virtual screening.96 The sensitivity to 76 was descreased by knockdown of mutant IDH1 in HT1080 cells.96 The tumor growth of HT1080-bearing CB-17/ICR-SCID mice was suppressed by 76 significantly following oral administration of 100 mg/kg and 50 mg/kg per day.96 76 was identified as a safe and effective mIDH1 inhibitor, occupying the allosteric site of mIDH1 and dose-dependently inhibits mIDH1 (IC50 = 37.86 ± 0.32 μM).96 3-Pyrazine-2-yl-oxazolidin-2-one Scaffold. Recently, our group has reported a series of allosteric mIDH1 inhibitors with a 3-pyrazine-2-yl-oxazolidin-2-one scaffold.97 All synthesized compounds could suppress D-2-HG production in cells transfected with IDH1-R132H and IDH1-R132C mutations at 50 μM.97 Among them, compound 3g (77, Figure 24) displayed inhibitory activity against IDH1-R132H and IDH1-R132C at 10 μM and 50 μM and weak inhibition against WT-IDH1, respectively.97 77 can effectively cross the blood−brain barrier (BBB) in a PAMPA-BBB model.97 3.2. IDH2 Mutant Inhibitors. 3.2.1. Agios Compounds. AGI-6780 (78, Figure 25), developed by Agios Pharmaceuticals, 8992



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potently and selectively inhibits IDH2 R140Q (IC50 = 170 nM).19,98 The cocrystal complex of IDH2 R140Q and 78 reveals that the inhibitor binds allosterically at the dimer interface of mIDH2.19,99 The slow, tight allosteric binding of 78 efficiently induced the differentiation of TF-1 erythroleukemia and primary human AML cells in vitro.19 AG-221. By use of a high-throughput screen based on a IDH2 R140Q homodimer, AG-221 (79, Figure 26), also known as

CC-90007 or enasidenib, was identified as an orally available, selective, and reversible mIDH2 inhibitor with IC50 values of 4.0 nM against IDH2 R140Q and 340 nM against WT-IDH2.100,101 It binds at an allosteric site within the IDH2 R140Q homodimer interface and blocks the mutant enzyme in an open conformation.101 It was developed by Agios in 2009 and then licensed to Celgene for further development.102 Cianchetta et al. applied for a patent to highlight the importance of the 1,3,5-triazine-2,4-diamine 8993



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core for mIDH2 inhibitors (79−84, Figure 26).103 These inhibitors are claimed to be therapeutically effective against IDH2-mutated tumor types, as evidenced by their activities against IDH2 R172K and R140Q (IC50 ≤ 100 nM) and their significant reduction of 2-HG production in U87-MG cells harboring IDH2 mutations (IC50 ≤ 100 nM).103 In a doseescalation phase I clinical trial, administration of 79 specifically reduced D-2-HG concentrations (∼90%), thereby inhibiting proliferation and inducing differentiation in cancer cells (NCT02577406). Furthermore, treatment with 79 rapidly reversed histone hypermethylation in both gliomas and leukemia.103 Phase I/II clinical studies with 79 alone or in combination with 4 in hematologic cancers or refractory advanced solid tumors are currently performing enrollment (NCT01915498, NCT02273739 and NCT02677922).104−106 On August 1 2017, 79 was approved by the FDA as a first-in-class drug targeting cancer metabolism for the treatment of IDH2-mutated relapsed/ refractory AML. 3.2.2. Teligene Compounds. Novel mIDH2 inhibitors with heterocyclic scaffolds were reported by scientists from Teligene. Enzymatic assays indicated that compound 85 (Figure 27) exhibited better inhibition than 79 against mIDH2 with an IC50 of 262 nM.107 It also suppressed the mutant kinases ALK

(L1152R), AXL (R499C), BRAF (G464V), and c-MER (A708S) at 10 μM.107 Compound 85 displayed higher solubility than 79 at both pH 4 and 7.107 3.2.3. Neuform Compounds. Neuform Pharmaceuticals recently reported a series of novel deuterated compounds as mIDH2 inhibitors for the treatment of various hematologic malignancies. D8-Enasidenib (86, Figure 27), with the IC50 value of 0.360 μM, exhibits similar inhibition against IDH2 R140Q to 79 (IC50 = 0.362 μM).108 It also showed greater metabolic stability than 79 in rat and human liver microsomes.108 PK studies suggested that 86 increased drug exposure (based on half-life time and AUC) in cynomolgus monkeys at 1 mg/kg iv compared with the effects of 79.108 3.2.4. Chia Tai Tianqing Compounds. Recently, a series of 1,3,5-triazine derivatives was discovered by Jiangsu Chia Tai Tianqing Pharmaceutical Co. and collaborators for the treatment of mIDH2-induced cancers. Compound 87 (Figure 28) not only showed significant inhibition against IDH2 R172K (IC50 = 31.69 nM) but also exhibited better PK properties than 79 in rats.109 Other potent derivatives of 87 (88−90) with IC50 values of less than 50 nM are shown in Figure 28.109 3.2.5. Jiangsu Provincial Academy of Traditional Chinese Medicine (JSATCM) Compounds. Scientists from Jiangsu Provincial Academy of Traditional Chinese Medicine (JSATCM) reported a patent for novel IDH2 inhibitors (91−96), in which compound 91 (Figure 29) inhibited IDH2 R140Q and IDH2 R172K with IC50 values of 0.041 μM and 0.1 μM or less, respectively, and exhibited better selectivity than 78 against WT-IDH2 in NADPH depletion assays.110 3.2.6. Sichuan University (SCU) Compounds. A series of 2,4,6-trisubstituted pyridine derivatives of 79 were identified by Sichuan University (SCU) as potent mIDH2 inhibitors. Among them, compound 97 (Figure 30) exhibited approximately 1-fold better inhibitory activity than 79 against IDH2 R140Q with an


Figure 31. Chemical structures of compounds 98−102. 8994



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IC50 of 54.6 nM.111,112 Excitingly, enzymatic assays demonstrated that compound 97 had high selectivity, >550-fold, for WT-IDH2 and WT-IDH1.111,112 3.3. Dual mIDH1/2 Inhibitors. 3.3.1. Agios Pharmaceuticals Compounds. AG-881 (98, vorasidenib, Figure 31) is an orally available, brain penetrant second-generation dual mIDH1/2 inhibitor.113 It exhibits nanomolar inhibition of D-2-HG with IC50 ranges of 0.04−22 nM against IDH1 R132C, IDH1 R132G, IDH1 R132H, and IDH1 R132S and 7−14 nM against IDH2 R140Q and 130 nM against IDH2 R172K.114 In addition, 98 has strong antiproliferative activity against human glioblastoma U-87 MG pLVX-IDH2 R140Q-neo, fibrosarcoma HT-1080, and neurosphere TS603 cells, all with IC50 values of less than 50 nM.113,114 In pharmacological studies, 98 exhibited excellent brain penetration and dose-dependently reduced D-2-HG levels.113 In pharmacokinetics studies, 98 showed rapid oral absorption and relatively low total body plasma clearance in mice (0.406 L h−1 kg−1) and rats (0.289 L h−1 kg−1).113,114 Recently, 98 entered a phase I clinical trial in patients with advanced solid tumors to investigate its PK/PD, safety, and clinical activity (NCT02481154). Another phase I clinical trial is focusing on patients with mIDH1/2 advanced hematologic cancers (NCT02492737). Excitingly, a phase I study of 98 and 4 in glioma will soon begin to evaluate the suppression of 2-HG in IDH1 mutant gliomas in resected tumor tissue after presurgical treatment with 98 or 4 (NCT03343197). Other representative compounds (99−102) from the patent (WO 2015003640) with IC50 values of less than 50 nM against mIDH1 and mIDH2 are shown in Figure 31.114 3.3.2. Evotec Compounds. Hay and colleagues at Evotec and Debiopharm reported 103 and 104 (Figure 32) to be efficient dual mIDH1/2 inhibitors with IC50 values of 2 nM against IDH1 R132H and 6 nM against IDH2 R172K.115 However, the two analogs 105 and 106 exhibited strong inhibition only of IDH1 R132H (IC50 = 28 nM and 29 nM, respectively).115

the active site. The conformation caused by the change of equilibrium owns the high affinity for NADPH.14 The loss of saltbridge interactions between the guanidinium of R132 and the α/β carboxylates of isocitrate, changes in the network that coordinates, and the reorganization of the active site are discovered in the examination of the catalytic pocket.14 The single R132H mutation results in formation of a distinct active site compared to WT- IDH1.14 Although the mutations affect the substrate site, allosteric sites play essential roles in the development of mIDH1 inhibitors. By contrast, the conformation of mIDH2 is closed and only one closed binding site has been reported.116 This difference leads to the selectivity of mIDH1 inhibitors over mIDH2. Some distinct binding modes of mIDH1 inhibitors at the active sites have been reported, but they still need to be more deeply understood. In addition, potential binding sites of other mIDH1 inhibitors, including 1, may be revealed in the future. Compared to mIDH1, an allosteric site has been described on mIDH2 which lies along the dimer interface and displayed non-time-dependent and noncompetitive inhibition versus α-KG.116 This insight might guide the discovery of mIDH2 inhibitors. 4.1. mIDH1 Binding Sites. 4.1.1. Substrate Site (Isocitrate Active Site). Two ligands (ICT and α-KG) bind to IDH1 R132H. The ICT substrate lies in the deep cleft binding site I, formed by residues Thr77, Ser94, Asn96, Gly97, Arg100, Arg109, and Asn101 (Figure 33). The binding site of 16 lies adjacent to the ICT binding pocket, which has also been referred to as a “bed surface”.62 Its two partially negatively charged oxygen atoms were found to form hydrogen bonds with the positively charged side chains of Arg100 and Asn101.62 On the basis of the X-ray crystallographic data (PDB code 4I3L), the excellent selectivity of these mIDH1 inhibitors (16−18) is attributed to this unique binding site.62 4.1.2. Allosteric Site (Divalent Magnesium Site). The first cocrystal structure of a mIDH1-24 complex (PDB code 4UMX) was published by Deng et al. in 2014 (Figure 33).70 Compound 24 strongly binds at the special allosteric site (also called the divalent magnesium site) of mIDH1, forming a direct hydrogen bond with Asp279. According to previous biological studies, three aspartate residues (Asp275 and Asp279 in one subunit and Asp252 in another subunit) are essential to form the chelation

4. BINDING MODES OF mIDH1/2 INHIBITORS It was reported that not only IDH1 R132H but also R132C, R132L, R132S mutations lead to a gain-function for NADPHdependent reduction of α-KG.14 The mutations of R132 result in the effect on conformation equilibrium and the reorganization of 8995



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Figure 33. The mIDH1 active sites are depicted in purple, red, blue, green, and yellow. Around the active sites, different inhibitors (SYC-435 (16, PDB code 4I3L), VVS (24, PDB code 4UMX), GSK321 (14, PDB code 5DE1), IDH889 (29, PDB code 5TQH), IDH146 and 26 (PDB code 5L57)) are shown and color-coded by their corresponding binding sites. The specific drug−target interactions between these inhibitors and mIDH1 are shown below, in which the green solid lines represent the π−π interactions and the yellow dotted lines represent the hydrogen bond interactions.

complex with the divalent magnesium ion.70 This finding suggested that 24 might compete against Mg2+ in ion cofactor binding, further preventing mIDH1 from maintaining a catalytically competent state. These results point to a double role of the divalent metal ion pocket in the discovery and optimization of more small-molecule selective inhibitors of mIDH1. 4.1.3. Second Allosteric Site (Seg-2 Active Site). The complex of compound 14 bound to mIDH1 was crystallographically determined (PDB code 5DE1) (Figure 33).59,60 It revealed that 14 binds in an allosteric site surrounded by the Seg-2 polypeptide

chain and other residues. Biochemical studies showed that the Seg-2 chain is an intrinsically disordered loop but adopts a helical conformation in the presence of α-KG. Compound 14 forms strong electrostatic interactions and hydrogen bonds with the Val281 and Gly284 residues in the Seg-2 region of mIDH1, blocking the loop-to-helix transition while forming the ternary complex.70 4.2. Allosteric Site in mIDH2. Recently, an important crystallographic study revealed AG-221 (79, PDB code 5I96) bound to an allosteric site located within the homodimer 8996



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Figure 34. An allosteric site in IDH2 R140Q is depicted in the purple circle. Around it, two mIDH2 inhibitors AGI-6780 (78, PDB code 4JA8) and AG-221 (79, PDB code 5I96) are shown. The specific drug−target interactions between these inhibitors and mIDH1 are shown below, in which the yellow dotted lines represent the hydrogen bond interactions and the green dotted lines represent the halogen bond interactions.

defects of the reported mIDH1/2 inhibitors and to more effectively treat patients with IDH1/2-mutated tumors.

interface of IDH2 R140Q, to which the selective mIDH2 inhibitor AGI-6780 (78, PDB code 4JA8) also binds (Figure 34).116 This deeply buried pocket is encapsulated by four helices (α9, α10, α9, α10′) lining the sides, two loops (L1, L1′), and the Y311−D312 interaction pairs capping the ends. Both 78 and 79 are anchored by multiple hydrogen bonds (Q316, Q316′, D312) and hydrophobic interactions within this pocket. They exhibit uncompetitive inhibition with respect to the NADPH cofactor and are among the slow-on/slow-off inhibitors of IDH2 R140Q.

6. PERSPECTIVE Currently, mIDH1/2 and the “oncometabolite” 2-HG have attracted increasing attention for cancer therapy. With advancing progress in understanding their biological mechanism, a variety of mIDH1/2 inhibitors have been developed, and AG-221 has been approved for clinical use. However, some issues still need to be resolved. First, almost all reported mIDH2 inhibitors were optimized from the scaffolds of AG-221 or AGI-6780. Thus, identification of novel scaffolds for mIDH2 inhibitors is in demand. Second, the IDH2 R172K mutation is related to certain specific tumors; however, little research work has been reported on selective inhibitors of IDH2 R172K.75,115 The crystal structure of the IDH2 R172K enzyme and its specific inhibitors are worthy of deeper investigation. Finally, clinical trials suggest that mIDH1 inhibitors alone are likely not sufficient for treating IDH-mutated tumors as monotherapy, especially glioma. Therefore, reasonable combinations with other anticancer drugs may be therapeutically beneficial.117−120 It was reported that mutant IDH1 lowered NAD+ levels by downregulating Naprt1, the rate-limiting enzyme in NAD+ biosythesis, sensitizing to NAD+ depletion via concomitant inhibition of NAMPT, the rate-limiting enzyme in NAD+

5. CONCLUSION Metabolic reprogramming is a fundamental aspect of cancer cells, and strong evidence has indicated that somatic IDH1/2 mutations contribute to glioma, advanced hematologic malignancies, and some solid tumors. Mutated forms of IDH1/2 represent promising targets for cancer therapy. This review highlights the research progress involving mIDH1/2 inhibitors, including their efficacy, selectivity, and clinical application (Table 1S). Structurally, mIDH1 inhibitors include more reported ligands with more diverse scaffolds than those of mIDH2. The mIDH2 inhibitor AG-221 is the first marketed drug for the treatment of IDH2-mutated AML. Its approval has led to a better understanding of the role of these mutant metabolic enzymes and their corresponding metabolites in tumorigenesis. Importantly, new strategies are needed to further overcome the 8997



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salvage synthesis pathway. NAD+ depletion activated the intracellular energy sensor AMPK, triggered autophagy, and resulted in cytotoxicity. Thus, IDH1 mutant cancers are vulnerable to NAMPT inhibitors and combination of mIDH1 inhibitors and NAMPT inhibitors may be beneficial in cancer therapy.121,122 This discovery provides new insights for the development of mIDH1 and NAMPT dual inhbitors and the treatment of IDH-mutant cancers. In addition, combination with two DNA alkylating agents procarbazine and CCNU/lomustine, and a microtubule poison vincristine may benefit patients with IDHmutant low-grade glioma and prolong their survival.120 Recently, a new study indicated that gliomas with IDH1 mutations are particularly sensitive to Bcl-xL inhibition. Therefore, the addition of Bcl-xL inhibitors such as ABT263 may be efficacious for mIDH1-mutated tumors.123 Overall, due to mutations in IDH1/2 being associated with some metabolic pathways, novel treatment strategies such as combining mIDH1/2 inhibitors and other anticancer drugs may benefit patients with IDH-mutated tumors.

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Andreas von Deimling obtained his MD from the University of Freiburg in 1988. He conducted postdoctoral research at Harvard University from 1990 to 1992. Currently, he is the Chairman and a Full Professor in Neuropathology at the University of Heidelberg and Head of the Clinical Cooperation Unit Neuropathology at the German Cancer Research Center (DKFZ). He has published more than 400 peerreviewed papers with over 33 000 citations. His main research focus is on the pathology and molecular genetics of tumors of the central and peripheral nervous systems. Xiaoming Zha obtained his Bachelor’s degree in Pharmaceutical Chemistry in 2002 and his Ph.D. in Medicinal Chemistry in 2007 at CPU. From 2013 to 2014, he was engaged in organic synthesis research in Professor E. J. Corey’s group at Harvard University as a CSCsponsored visiting scholar. He has published more than 20 peerreviewed papers and applied for 10 patents. His research interests mainly focus on the identification of small molecules that target cancer metabolism, including mutant IDH1/2 and epigenetic regulation such as histone demethylases.

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ACKNOWLEDGMENTS We are grateful for the support from the Natural Science Foundation of Jiangsu Province of China (Grant BK20161458), the “Six Talent Peaks” Project of Jiangsu Province (Grant 2016YY-042), the Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant KYCX17_0721), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b00159. Mutant IDH1/2 in clinical trials and physical properties of some mIDH1/2 inhibitors (PDF)

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AUTHOR INFORMATION

Corresponding Author

ABBREVIATIONS USED IDH, isocitrate dehydrogenase; mIDH, mutant isocitrate dehydrogenase; ICT, isocitric acid; α-KG, α-ketoglutaric acid; 2-HG, 2-hydroxyglutaric acid; D-2-HG, (D)-2-hydroxyglutarate which is equivalent to (−)-2-hydroxglutarate and (R)-2hydroxyglutarate; L-2-HG, (L)-2-hydroxyglutarate which is equivalent to (+)-2-hydroxglutarate and (S)-2-hydroxyglutarate; R132H, Arg132 mutation to His; R132C, Arg132 mutation to Cys; T, threonine; R140Q, Arg140 mutation to Gln; H, histidine; K, lysine; M, methionine; V, valine; W, tyrosine; WT, wild type; HIF-1α, hypoxia-inducible factor 1α; LOH 19q, loss of heterozygosity on chromosome 19q; LOH 22q, loss of heterozygosity on chromosome 22q; TP53, tumor protein 53; DNMT3A, DNA methyltransferase 3A; TET2, tet methylcytosine dioxygenase 2; HNF-4α, hepatocyte nuclear factor 4α; NPM1, nucleophosmin 1 gene; MDS/MPN, myelodysplastic/ myeloproliferative neoplasm; BBB, blood−brain barrier; PK/ PD, pharmacokinetic/pharmacodynamic; FLT3-ITD, FMS-like tyrosine kinase 3-internal tandem duplication; CD38, cluster of differentiation 38; NAPRT1, nicotinic acid phosphoribosyltransferase; NAMPT, nicotinamide phosphoribosyltransferase

*Phone: +86-25-83271057. Fax: +86-25-83271142. E-mail: [email protected]. Author Contributions ⊥

T.M., F.Z., and S.P. contributed equally.

Notes

The authors declare no competing financial interest. Biographies Tianfang Ma received his Bachelor’s degree from China Pharmaceutical University in 2015. In the same year, he studied under Prof. Xiaoming Zha for his Master’s degree. His research mainly focuses on the discovery and optimization of small molecules that target cancer metabolism. Fangxia Zou obtained her Master’s degree from China Pharmaceutical University in June 2017. As a Master’s graduate, she mainly conducted the molecular simulation and drug design of the small molecules targeting mutant IDH1/2 under the supervision of Prof. Xiaoming Zha. Stefan Pusch obtained his Diploma in Biology from the University of Cologne/Max-Planck Institute for Plant Breeding Research in 2004. In 2008, he graduated from the same institute. He joined the Clinical Cooperation Unit Neuropathology at the German Cancer Research Center (DKFZ) in Heidelberg as a postdoc in 2009. Beginning in 2011, he focused on drug discovery for mutant IDH1/2 tumors.

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REFERENCES

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