Recent advances of IDH1 mutant inhibitor in cancer therapy

Isocitrate dehydrogenase (IDH) is the key metabolic enzyme that catalyzes the conversion of isocitrate to α-ketoglutarate (α-KG). Two main types of IDH1 and IDH2 are present in humans. In recent years, mutations in IDH have been observed in several tumors, including glioma, acute myeloid leukemia, and chondrosarcoma. Among them, the frequency of IDH1 mutations is higher than IDH2. IDH1 mutations have been shown to increase the conversion of α-KG to 2-hydroxyglutarate (2-HG). IDH1 mutation-mediated accumulation of 2-HG leads to epigenetic dysregulation, altering gene expression, and impairing cell differentiation. A rapidly emerging therapeutic approach is through the development of small molecule inhibitors targeting mutant IDH1 (mIDH1), as evidenced by the recently approved of the first selective IDH1 mutant inhibitor AG-120 (ivosidenib) for the treatment of IDH1-mutated AML. This review will focus on mIDH1 as a therapeutic target and provide an update on IDH1 mutant inhibitors in development and clinical trials.

[1]  C. Schofield,et al.  Roles of metal ions in the selective inhibition of oncogenic variants of isocitrate dehydrogenase 1 , 2021, Communications Biology.

[2]  Peixuan Li,et al.  Targeting protein arginine methyltransferase 5 in cancers: Roles, inhibitors and mechanisms. , 2021, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[3]  S. Choe,et al.  Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation , 2021, JAMA oncology.

[4]  Qianqian Wang,et al.  Selectively targeting individual bromodomain: drug discovery and molecular mechanisms. , 2021, Pharmacological research.

[5]  Ri Zhang,et al.  Additional mutations in IDH1/2‐mutated patients with acute myeloid leukemia , 2021, International journal of laboratory hematology.

[6]  E. Maher,et al.  Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial , 2021, Clinical Cancer Research.

[7]  H. Döhner,et al.  Towards precision medicine for AML , 2021, Nature Reviews Clinical Oncology.

[8]  Shuai Bian,et al.  QSAR analysis of 3-pyrimidin-4-yl-oxazolidin-2-one derivatives isocitrate dehydrogenase inhibitors using Topomer CoMFA and HQSAR methods , 2021, Molecular Diversity.

[9]  Mindy I. Davis,et al.  Discovery and Optimization of 2H-1λ2-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer. , 2021, Journal of medicinal chemistry.

[10]  E. Traer,et al.  IDH Inhibitors in AML—Promise and Pitfalls , 2021, Current Hematologic Malignancy Reports.

[11]  Wenzhe Ma,et al.  Identification and characterization of a novel mutant isocitrate dehydrogenase 1 inhibitor for glioma treatment. , 2021, Biochemical and biophysical research communications.

[12]  H. Dombret,et al.  Prognostic significance of concurrent gene mutations in intensively treated patients with IDH-mutated AML, an ALFA study. , 2021, Blood.

[13]  D. Schiff,et al.  Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors , 2021, Clinical Cancer Research.

[14]  J. Costello,et al.  Early Noninvasive Metabolic Biomarkers of Mutant IDH Inhibition in Glioma , 2021, Metabolites.

[15]  Yuping Tang,et al.  Discovery of Novel IDH1 Inhibitor Through Comparative Structure-Based Virtual Screening , 2020, Frontiers in Pharmacology.

[16]  H. Schwalbe,et al.  Non-Invasive Measurement of Drug and 2-HG Signals Using 19F and 1H MR Spectroscopy in Brain Tumors Treated with the Mutant IDH1 Inhibitor BAY1436032 , 2020, Cancers.

[17]  M. Gilbert,et al.  Sphingolipid Pathway as a Source of Vulnerability in IDH1mut Glioma , 2020, Cancers.

[18]  R. Geffers,et al.  IDH1/2 mutations in acute myeloid leukemia patients and risk of coronary artery disease and cardiac dysfunction—a retrospective propensity score analysis , 2020, Leukemia.

[19]  H. Döhner,et al.  Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study. , 2020, Blood.

[20]  H. Jeong,et al.  Discovery of a Novel Chemical Scaffold Against Mutant Isocitrate Dehydrogenase 1 (IDH1) , 2020, AntiCancer Research.

[21]  Kyung-Sub Moon,et al.  Frequency and Prognostic Value of IDH Mutations in Korean Patients With Cholangiocarcinoma , 2020, Frontiers in Oncology.

[22]  Bingyan Wu,et al.  Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results , 2020, Leukemia.

[23]  R. Novoa,et al.  Differentiation syndrome during ivosidenib treatment with immunohistochemistry showing isocitrate dehydrogenase R132H mutation , 2020, Journal of cutaneous pathology.

[24]  A. Zhu,et al.  Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. , 2020, The Lancet. Oncology.

[25]  Hua Yang,et al.  Clinical pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation , 2020, Cancer Chemotherapy and Pharmacology.

[26]  M. Gilbert,et al.  IDH mutation in glioma: molecular mechanisms and potential therapeutic targets , 2020, British Journal of Cancer.

[27]  S. Yip,et al.  Characterisation of isocitrate dehydrogenase 1/isocitrate dehydrogenase 2 gene mutation and the d‐2‐hydroxyglutarate oncometabolite level in dedifferentiated chondrosarcoma , 2020 .

[28]  Xizhe Li,et al.  Immunotherapy for glioma: current management and future application. , 2020, Cancer letters.

[29]  A. Poloni,et al.  The Time Has Come for Targeted Therapies for AML: Lights and Shadows , 2020, Oncology and Therapy.

[30]  Mark T. Kershaw,et al.  Structure-based design and identification of FT-2102 (olutasidenib), a potent mutant-selective IDH1 inhibitor. , 2020, Journal of medicinal chemistry.

[31]  I. Mellinghoff,et al.  Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma , 2020, ACS medicinal chemistry letters.

[32]  S. Cardaci,et al.  The TCA Cycle at the Crossroad between Cancer and Immunity. , 2019, Antioxidants & redox signaling.

[33]  Jidong Zhu,et al.  Discovery of new small molecule inhibitors targeting isocitrate dehydrogenase 1 (IDH1) with blood-brain barrier penetration. , 2019, European journal of medicinal chemistry.

[34]  Sun Li,et al.  I-8, a novel inhibitor of mutant IDH1, inhibits cancer progression in vitro and in vivo. , 2019, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[35]  C. Luo,et al.  Licochalcone A suppresses the proliferation of sarcoma HT-1080 cells, as a selective R132C mutant IDH1 inhibitor. , 2019, Bioorganic & medicinal chemistry letters.

[36]  O. Sampetrean,et al.  A Potent Blood–Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model , 2019, Molecular Cancer Therapeutics.

[37]  T. Soga,et al.  Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma , 2019, Oncogene.

[38]  F. Schumacher,et al.  Vitamin C in combination with inhibition of mutant IDH1 synergistically activates TET enzymes and epigenetically modulates gene silencing in colon cancer cells , 2019, Epigenetics.

[39]  C. Luo,et al.  Discovery of DC_H31 as potential mutant IDH1 inhibitor through NADPH-based high throughput screening. , 2019, Bioorganic & medicinal chemistry.

[40]  M. Heuser,et al.  In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site , 2019, Leukemia.

[41]  G. Wang,et al.  A model system for studying the DNMT3A hotspot mutation (DNMT3AR882) demonstrates a causal relationship between its dominant-negative effect and leukemogenesis. , 2019, Cancer research.

[42]  E. Barragán,et al.  IDH1-mutated relapsed or refractory AML: current challenges and future prospects , 2019, Blood and lymphatic cancer : targets and therapy.

[43]  Mark T. Kershaw,et al.  Discovery and Optimization of Quinolinone Derivatives as Potent, Selective and Orally Bioavailable mutant Isocitrate Dehydrogenase 1 (mIDH1) Inhibitors. , 2019, Journal of medicinal chemistry.

[44]  D. Placantonakis,et al.  Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics , 2019, Front. Oncol..

[45]  P. Wen,et al.  Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors , 2019, Investigational New Drugs.

[46]  Jian-rong Gao,et al.  Synthesis and biological evaluation of 3-aryl-4-indolyl-maleimides as potent mutant isocitrate dehydrogenase-1 inhibitors. , 2019, Bioorganic & medicinal chemistry.

[47]  Sarah E. Dorff,et al.  FDA Approval Summary: Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation , 2019, Clinical Cancer Research.

[48]  Min Huang,et al.  Discovery and structure-activity-relationship study of novel imidazole cyclopropyl amine analogues for mutant isocitric dehydrogenase 1 (IDH1) inhibitors. , 2018, Bioorganic & Medicinal Chemistry Letters.

[49]  Yongcheng Song,et al.  Inhibition of Mutated Isocitrate Dehydrogenase 1 in Cancer. , 2018, Medicinal chemistry (Shariqah (United Arab Emirates)).

[50]  C. Yun,et al.  Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2. , 2018, Biochemical and biophysical research communications.

[51]  Lixia Chen,et al.  Steroids from Ganoderma sinense as new natural inhibitors of cancer-associated mutant IDH1. , 2018, Bioorganic chemistry.

[52]  Yu-ting Su,et al.  Perspectives on IDH Mutation in Diffuse Gliomas. , 2018, Trends in cancer.

[53]  Jian-rong Gao,et al.  3‐(7‐Azaindolyl)‐4‐indolylmaleimides as a novel class of mutant isocitrate dehydrogenase‐1 inhibitors: Design, synthesis, and biological evaluation , 2018, Archiv der Pharmazie.

[54]  B. Firestone,et al.  Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Orally Bioavailable and Brain Penetrant Mutant IDH1 Inhibitors. , 2018, ACS medicinal chemistry letters.

[55]  Qinxi Li,et al.  IDH1 Arg-132 mutant promotes tumor formation through down-regulating p53 , 2018, The Journal of Biological Chemistry.

[56]  K. Srivenugopal,et al.  Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies , 2018, Cancers.

[57]  S. Gross,et al.  Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers , 2018, ACS medicinal chemistry letters.

[58]  Y. Xiong,et al.  Metabolism, Activity, and Targeting of D-and L-2-Hydroxyglutarates , 2018, Trends in cancer.

[59]  A. von Deimling,et al.  Design, synthesis and biological activity of 3-pyrazine-2-yl-oxazolidin-2-ones as novel, potent and selective inhibitors of mutant isocitrate dehydrogenase 1. , 2017, Bioorganic & medicinal chemistry.

[60]  A. von Deimling,et al.  Identification of novel allosteric inhibitors of mutant isocitrate dehydrogenase 1 by cross docking-based virtual screening. , 2017, Bioorganic & medicinal chemistry letters.

[61]  Min Huang,et al.  Discovery and structure-activity-relationship study of novel conformationally restricted indane analogues for mutant isocitric dehydrogenase 1 (IDH1) inhibitors. , 2017, Bioorganic & medicinal chemistry letters.

[62]  B. Firestone,et al.  Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor. , 2017, ACS medicinal chemistry letters.

[63]  S. Gokul,et al.  Research Highlights BAY 1436032: A Novel Pan-mutant IDH1 Inhibitor Extends Survival of Mice with Experimental Brain Tumors. , 2017, CNS & neurological disorders drug targets.

[64]  S. Su,et al.  Isocitrate Dehydrogenase Mutation and (R)-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Development. , 2017, Annual review of biochemistry.

[65]  Jiahuai Han,et al.  2-HG Inhibits Necroptosis by Stimulating DNMT1-Dependent Hypermethylation of the RIP3 Promoter. , 2017, Cell reports.

[66]  H. Colman,et al.  Glioma Subclassifications and Their Clinical Significance , 2017, Neurotherapeutics.

[67]  Amar Deep Sharma,et al.  Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo , 2017, Leukemia.

[68]  Michael D. Jones,et al.  Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1. , 2017, ACS medicinal chemistry letters.

[69]  M. Wigglesworth,et al.  Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells. , 2016, Journal of medicinal chemistry.

[70]  S. Schreiber,et al.  Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1. , 2016, ACS medicinal chemistry letters.

[71]  Mindy I. Davis,et al.  Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery , 2016, Cell.

[72]  C. Perou,et al.  Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents. , 2015, Cell reports.

[73]  Nicholas D. Adams,et al.  New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. , 2015, Nature chemical biology.

[74]  B. Zheng,et al.  Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds. , 2015, Journal of medicinal chemistry.

[75]  Y. Keum,et al.  Identification of a New Selective Chemical Inhibitor of Mutant Isocitrate Dehydrogenase-1 , 2015, Journal of cancer prevention.

[76]  A. Isacchi,et al.  Effective immuno-targeting of the IDH1 mutation R132H in a murine model of intracranial glioma , 2015, Acta neuropathologica communications.

[77]  Dietmar Hoffmann,et al.  Selective Inhibition of Mutant Isocitrate Dehydrogenase 1 (IDH1) via Disruption of a Metal Binding Network by an Allosteric Small Molecule , 2014, The Journal of Biological Chemistry.

[78]  B. Zheng,et al.  Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases: Synthesis, Structure–Activity Relationship, and Selective Antitumor Activity , 2014, Journal of medicinal chemistry.

[79]  M. Velez,et al.  Isocitrate dehydrogenase mutations in chondrosarcoma: the crossroads between cellular metabolism and oncogenesis , 2014, Current opinion in oncology.

[80]  S. Stevanović,et al.  A vaccine targeting mutant IDH1 induces antitumour immunity , 2014, Nature.

[81]  Yan Ma,et al.  [Research progress on genes associated with transformation of myelodysplastic syndromes to acute myeloid leukemia]. , 2014, Zhongguo shi yan xue ye xue za zhi.

[82]  Mindy I. Davis,et al.  Biochemical, Cellular, and Biophysical Characterization of a Potent Inhibitor of Mutant Isocitrate Dehydrogenase IDH1* , 2014, The Journal of Biological Chemistry.

[83]  Ulrich Lehmann,et al.  Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. , 2013, Blood.

[84]  Hai Yan,et al.  Releasing the block: setting differentiation free with mutant IDH inhibitors. , 2013, Cancer cell.

[85]  B. Prasad,et al.  Crystallographic Investigation and Selective Inhibition of Mutant Isocitrate Dehydrogenase. , 2013, ACS medicinal chemistry letters.

[86]  Mindy I. Davis,et al.  ML309: A potent inhibitor of R132H mutant IDH1 capable of reducing 2-hydroxyglutarate production in U87 MG glioblastoma cells , 2013 .

[87]  Fang Wang,et al.  An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells , 2013, Science.

[88]  W. Kaelin,et al.  What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. , 2013, Genes & development.

[89]  Dik-Lung Ma,et al.  Drug repositioning by structure-based virtual screening. , 2013, Chemical Society reviews.

[90]  John H. Sampson,et al.  Enzyme Redesign Guided by Cancer-Derived IDH1 Mutations , 2012, Nature chemical biology.

[91]  S. Gross,et al.  Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo. , 2012, ACS medicinal chemistry letters.

[92]  R. Verhaak,et al.  Transformation by the R Enantiomer of 2-Hydroxyglutarate Linked to EglN Activation , 2012, Nature.

[93]  R. Klose,et al.  The oncometabolite 2‐hydroxyglutarate inhibits histone lysine demethylases , 2011, EMBO reports.

[94]  E. Jungheim,et al.  Fertility treatment in women with polycystic ovary syndrome: a decision analysis of different oral ovulation induction agents. , 2010, Fertility and sterility.

[95]  Jianping Ding,et al.  Molecular mechanisms of “off-on switch” of activities of human IDH1 by tumor-associated mutation R132H , 2010, Cell Research.

[96]  E. Tobinick.  The value of drug repositioning in the current pharmaceutical market. , 2009, Drug news & perspectives.

[97]  D. Busam,et al.  An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2008, Science.

[98]  G. Parmigiani,et al.  The Consensus Coding Sequences of Human Breast and Colorectal Cancers , 2006, Science.

[99]  L. Prasad,et al.  Substrate‐free structure of a monomeric NADP isocitrate dehydrogenase: An open conformation phylogenetic relationship of isocitrate dehydrogenase , 2006, Proteins.

[100]  Isao Tanaka,et al.  Structure of the monomeric isocitrate dehydrogenase: evidence of a protein monomerization by a domain duplication. , 2002, Structure.

[101]  D. Holtkamp,et al.  Development, pharmacology and clinical experience with clomiphene citrate. , 1996, Human reproduction update.

[102]  P. Vandekerckhove,et al.  WITHDRAWN: Clomiphene citrate for ovulation induction in women with oligo-amenorrhoea. , 1996, The Cochrane database of systematic reviews.

[103]  D E Koshland,et al.  Structure of a bacterial enzyme regulated by phosphorylation, isocitrate dehydrogenase. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[104]  S. Yip,et al.  Characterisation of isocitrate dehydrogenase 1/isocitrate dehydrogenase 2 gene mutation and the d‐2‐hydroxyglutarate oncometabolite level in dedifferentiated chondrosarcoma , 2020, Histopathology.

[105]  G. Reifenberger,et al.  Glioma , 2015, Nature Reviews Disease Primers.

[106]  P. Gadal,et al.  Structure, functions and regulation of NAD and NADP dependent isocitrate dehydrogenases in higher plants and in other organisms , 1990 .