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Abstract

Isocitrate Dehydrogenases (IDH) are ubiquitous enzymes essential for cellular metabolism, including the Krebs cycle, glutamine metabolism, lipogenesis, and redox balance. Mutations in IDH1 and IDH2 are implicated in several tumors-gliomas, Acute Myeloid Leukemia (AML), cholangiocarcinoma-altering enzyme activity and causing the overproduction of 2-hydroxyglutarate (2-HG). This oncometabolite disrupts α-KG-dependent proteins, impairing key processes such as differentiation, division, and DNA repair. Understanding these genetic, biochemical, and clinical aspects has made IDH enzymes promising therapeutic targets, prompting the development of targeted inhibitors for tumors harboring IDH1 or IDH2 point mutations. Selective inhibitors like ivosidenib (AG-120) and enasidenib (AG-221), targeting mutant IDH1 and IDH2 respectively, block 2-HG production and induce differentiation, achieving clinical success - particularly in AML. However, resistance due to secondary mutations, especially in the allosteric binding site, remains a major obstacle. In response, novel approaches have emerged, such as covalent inhibitors like LY3410738, which irreversibly bind mutant residues, and dual inhibitors like vorasidenib (AG-881), which act on both IDH1 and IDH2 mutations and penetrate the blood-brain barrier for treating solid tumors. Still, many clinical factors must be considered. This review explores the current landscape of IDH-targeted therapies, emphasizing the need for novel inhibitors and highlighting innovative strategies, including the design of smaller, more potent molecules with favorable pharmacokinetics and the potential of drug repositioning. We underscore that discovering new antitumor compounds targeting IDH requires a collaborative effort across biomedical fields. These advancements aim to overcome resistance, broaden therapeutic options, and improve the effectiveness of IDH-targeted treatments.

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2025-09-16
2025-11-09

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References

  1. Koh H.J. Lee S.M. Son B.G. Lee S.H. Ryoo Z.Y. Chang K.T. Park J.W. Park D.C. Song B.J. Veech R.L. Song H. Huh T.L. Cytosolic NADP+-dependent isocitrate dehydrogenase plays a key role in lipid metabolism. J. Biol. Chem. 2004 279 38 39968 39974 10.1074/jbc.M402260200 15254034
    [Google Scholar]
  2. Lee S.H. Jo S.H. Lee S.M. Koh H.J. Song H. Park J.W. Lee W.H. Huh T.L. Role of NADP + ‐dependent isocitrate dehydrogenase (NADP + ‐ICDH) on cellular defence against oxidative injury by γ ‐rays. Int. J. Radiat. Biol. 2004 80 9 635 642 10.1080/09553000400007680 15586883
    [Google Scholar]
  3. Badur M.G. Muthusamy T. Parker S.J. Ma S. McBrayer S.K. Cordes T. Magana J.H. Guan K-L. Metallo C.M. Oncogenic R132 IDH1 mutations limit NADPH for de novo lipogenesis through (D) 2-hydroxyglutarate production in fibrosarcoma cells. Cell Reports 2018 25 4 1018 1026 10.1016/j.celrep.2018.09.074
    [Google Scholar]
  4. Golub D. Iyengar N. Dogra S. Wong T. Bready D. Tang K. Modrek A.S. Placantonakis D.G. Mutant isocitrate dehydrogenase inhibitors as targeted cancer therapeutics. Front. Oncol. 2019 9 417 10.3389/fonc.2019.00417 31165048
    [Google Scholar]
  5. Tommasini-Ghelfi S. Murnan K. Kouri F.M. Mahajan A.S. May J.L. Stegh A.H. Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease. Sci. Adv. 2019 5 5 eaaw4543 10.1126/sciadv.aaw4543 31131326
    [Google Scholar]
  6. Han S. Liu Y. Cai S.J. Qian M. Ding J. Larion M. Gilbert M.R. Yang C. IDH mutation in glioma: Molecular mechanisms and potential therapeutic targets. Br. J. Cancer 2020 122 11 1580 1589 10.1038/s41416‑020‑0814‑x 32291392
    [Google Scholar]
  7. Reitman Z.J. Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: Alterations at a crossroads of cellular metabolism. J. Natl. Cancer Inst. 2010 102 13 932 941 10.1093/jnci/djq187 20513808
    [Google Scholar]
  8. Nelson D.L. Lehninger A.L. Lehninger principles of biochemistry. Macmillan 2008
    [Google Scholar]
  9. Chesnelong C. Isocitrate dehydrogenase (IDH) mutation in gliomas. Next Generation Sequence Cancer Res. 2015 2 441 458 10.1007/978‑3‑319‑15811‑2_25
    [Google Scholar]
  10. Rather G.M. Pramono A.A. Szekely Z. Bertino J.R. Tedeschi P.M. In cancer, all roads lead to NADPH. Pharmacol. Ther. 2021 226 107864 10.1016/j.pharmthera.2021.107864 33894275
    [Google Scholar]
  11. Al-Khallaf H. Isocitrate dehydrogenases in physiology and cancer: Biochemical and molecular insight. Cell Biosci. 2017 7 1 37 10.1186/s13578‑017‑0165‑3 28785398
    [Google Scholar]
  12. Sun P. Liu Y. Ma T. Ding J. Structure and allosteric regulation of human NAD-dependent isocitrate dehydrogenase. Cell Discov. 2020 6 1 94 10.1038/s41421‑020‑00220‑7 33349631
    [Google Scholar]
  13. Pirozzi C.J. Yan H. The implications of IDH mutations for cancer development and therapy. Nat. Rev. Clin. Oncol. 2021 18 10 645 661 10.1038/s41571‑021‑00521‑0 34131315
    [Google Scholar]
  14. McMurry J. Begley T.P. The organic chemistry of biological pathways. Roberts and Company Publishers 2005
    [Google Scholar]
  15. Kotredes K.P. Razmpour R. Lutton E. Alfonso-Prieto M. Ramirez S.H. Gamero A.M. Characterization of cancer-associated IDH2 mutations that differ in tumorigenicity, chemosensitivity and 2-hydroxyglutarate production. Oncotarget 2019 10 28 2675 2692 10.18632/oncotarget.26848 31105869
    [Google Scholar]
  16. Sjöblom T. Jones S. Wood L.D. Parsons D.W. Lin J. Barber T.D. Mandelker D. Leary R.J. Ptak J. Silliman N. Szabo S. Buckhaults P. Farrell C. Meeh P. Markowitz S.D. Willis J. Dawson D. Willson J.K.V. Gazdar A.F. Hartigan J. Wu L. Liu C. Parmigiani G. Park B.H. Bachman K.E. Papadopoulos N. Vogelstein B. Kinzler K.W. Velculescu V.E. The consensus coding sequences of human breast and colorectal cancers. Science 2006 314 5797 268 274 10.1126/science.1133427 16959974
    [Google Scholar]
  17. Wood L.D. Parsons D.W. Jones S. Lin J. Sjöblom T. Leary R.J. Shen D. Boca S.M. Barber T. Ptak J. Silliman N. Szabo S. Dezso Z. Ustyanksky V. Nikolskaya T. Nikolsky Y. Karchin R. Wilson P.A. Kaminker J.S. Zhang Z. Croshaw R. Willis J. Dawson D. Shipitsin M. Willson J.K.V. Sukumar S. Polyak K. Park B.H. Pethiyagoda C.L. Pant P.V.K. Ballinger D.G. Sparks A.B. Hartigan J. Smith D.R. Suh E. Papadopoulos N. Buckhaults P. Markowitz S.D. Parmigiani G. Kinzler K.W. Velculescu V.E. Vogelstein B. The genomic landscapes of human breast and colorectal cancers. Science 2007 318 5853 1108 1113 10.1126/science.1145720 17932254
    [Google Scholar]
  18. Fathi A.T. Sadrzadeh H. Comander A.H. Higgins M.J. Bardia A. Perry A. Burke M. Silver R. Matulis C.R. Straley K.S. Yen K.E. Agresta S. Kim H. Schenkein D.P. Borger D.R. Isocitrate dehydrogenase 1 (IDH1) mutation in breast adenocarcinoma is associated with elevated levels of serum and urine 2-hydroxyglutarate. Oncologist 2014 19 6 602 607 10.1634/theoncologist.2013‑0417 24760710
    [Google Scholar]
  19. Chiang S. Weigelt B. Wen H.C. Pareja F. Raghavendra A. Martelotto L.G. Burke K.A. Basili T. Li A. Geyer F.C. Piscuoglio S. Ng C.K.Y. Jungbluth A.A. Balss J. Pusch S. Baker G.M. Cole K.S. von Deimling A. Batten J.M. Marotti J.D. Soh H.C. McCalip B.L. Serrano J. Lim R.S. Siziopikou K.P. Lu S. Liu X. Hammour T. Brogi E. Snuderl M. Iafrate A.J. Reis-Filho J.S. Schnitt S.J. IDH2 mutations define a unique subtype of breast cancer with altered nuclear polarity. Cancer Res. 2016 76 24 7118 7129 10.1158/0008‑5472.CAN‑16‑0298 27913435
    [Google Scholar]
  20. Minemura H. Takagi K. Sato A. Yamaguchi M. Hayashi C. Miki Y. Harada-Shoji N. Miyashita M. Sasano H. Suzuki T. Isoforms of IDH in breast carcinoma: IDH2 as a potent prognostic factor associated with proliferation in estrogen-receptor positive cases. Breast Cancer 2021 28 4 915 926 10.1007/s12282‑021‑01228‑x 33713004
    [Google Scholar]
  21. Hanahan D. Hallmarks of cancer: New dimensions. Cancer Discov. 2022 12 1 31 46 10.1158/2159‑8290.CD‑21‑1059 35022204
    [Google Scholar]
  22. Saha S.K. Parachoniak C.A. Bardeesy N. IDH mutations in liver cell plasticity and biliary cancer. Cell Cycle 2014 13 20 3176 3182 10.4161/15384101.2014.965054 25485496
    [Google Scholar]
  23. Senga S.S. Grose R.P. Hallmarks of cancer-the new testament. Open Biol. 2021 11 1 200358 10.1098/rsob.200358 33465324
    [Google Scholar]
  24. Wu L. Chai R. Zhao Z. Wang Q. Jiang T. Role of the tumor microenvironment in shaping IDH-wildtype glioma plasticity, and potential therapeutic strategies. Cancer Biol. Med. 2022 19 10 1423 1427 10.20892/j.issn.2095‑3941.2022.0363 36350003
    [Google Scholar]
  25. Watanabe T. Nobusawa S. Kleihues P. Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am. J. Pathol. 2009 174 4 1149 1153 10.2353/ajpath.2009.080958 19246647
    [Google Scholar]
  26. Juratli T.A. Kirsch M. Robel K. Soucek S. Geiger K. von Kummer R. Schackert G. Krex D. IDH mutations as an early and consistent marker in low-grade astrocytomas WHO grade II and their consecutive secondary high-grade gliomas. J. Neurooncol. 2012 108 3 403 410 10.1007/s11060‑012‑0844‑1 22410704
    [Google Scholar]
  27. Yang B. Zhong C. Peng Y. Lai Z. Ding J. Molecular mechanisms of “off-on switch” of activities of human IDH1 by tumor-associated mutation R132H. Cell Res. 2010 20 11 1188 1200 10.1038/cr.2010.145 20975740
    [Google Scholar]
  28. Harding J.J. Lowery M.A. Shih A.H. Schvartzman J.M. Hou S. Famulare C. Patel M. Roshal M. Do R.K. Zehir A. You D. Selcuklu S.D. Viale A. Tallman M.S. Hyman D.M. Reznik E. Finley L.W.S. Papaemmanuil E. Tosolini A. Frattini M.G. MacBeth K.J. Liu G. Fan B. Choe S. Wu B. Janjigian Y.Y. Mellinghoff I.K. Diaz L.A. Levine R.L. Abou-Alfa G.K. Stein E.M. Intlekofer A.M. Isoform switching as a mechanism of acquired resistance to mutant isocitrate dehydrogenase inhibition. Cancer Discov. 2018 8 12 1540 1547 10.1158/2159‑8290.CD‑18‑0877 30355724
    [Google Scholar]
  29. Xu X. Zhao J. Xu Z. Peng B. Huang Q. Arnold E. Ding J. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J. Biol. Chem. 2004 279 32 33946 33957 10.1074/jbc.M404298200 15173171
    [Google Scholar]
  30. Figueroa M.E. Abdel-Wahab O. Lu C. Ward P.S. Patel J. Shih A. Li Y. Bhagwat N. Vasanthakumar A. Fernandez H.F. Tallman M.S. Sun Z. Wolniak K. Peeters J.K. Liu W. Choe S.E. Fantin V.R. Paietta E. Löwenberg B. Licht J.D. Godley L.A. Delwel R. Valk P.J.M. Thompson C.B. Levine R.L. Melnick A. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010 18 6 553 567 10.1016/j.ccr.2010.11.015 21130701
    [Google Scholar]
  31. Xu W. Yang H. Liu Y. Yang Y. Wang P. Kim S.H. Ito S. Yang C. Wang P. Xiao M.T. Liu L. Jiang W. Liu J. Zhang J. Wang B. Frye S. Zhang Y. Xu Y. Lei Q. Guan K.L. Zhao S. Xiong Y. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 2011 19 1 17 30 10.1016/j.ccr.2010.12.014 21251613
    [Google Scholar]
  32. Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 2002 21 35 5427 5440 10.1038/sj.onc.1205600 12154405
    [Google Scholar]
  33. Ježek P. 2-Hydroxyglutarate in cancer cells. Antioxid. Redox Signal. 2020 33 13 903 926 10.1089/ars.2019.7902 31847543
    [Google Scholar]
  34. Du X. Hu H. The roles of 2-hydroxyglutarate. Front. Cell Dev. Biol. 2021 9 651317 10.3389/fcell.2021.651317 33842477
    [Google Scholar]
  35. Cai Z. Yang H. Yu Z. Su J. Zhang J. Ye Z. Hu K. Huang T. Zhou H. Efficacy and safety of IDH inhibitors in IDH-mutated cancers: A systematic review and meta-analysis of 4 randomized controlled trials. World J. Surg. Oncol. 2024 22 1 295 10.1186/s12957‑024‑03579‑z 39511636
    [Google Scholar]
  36. Popovici-Muller J. Saunders J.O. Salituro F.G. Travins J.M. Yan S. Zhao F. Gross S. Dang L. Yen K.E. Yang H. Straley K.S. Jin S. Kunii K. Fantin V.R. Zhang S. Pan Q. Shi D. Biller S.A. Su S.M. Su S.M. Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in Vivo. ACS Med. Chem. Lett. 2012 3 10 850 855 10.1021/ml300225h 24900389
    [Google Scholar]
  37. Dang L. White D.W. Gross S. Bennett B.D. Bittinger M.A. Driggers E.M. Fantin V.R. Jang H.G. Jin S. Keenan M.C. Marks K.M. Prins R.M. Ward P.S. Yen K.E. Liau L.M. Rabinowitz J.D. Cantley L.C. Thompson C.B. Vander Heiden M.G. Su S.M. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009 462 7274 739 744 10.1038/nature08617 19935646
    [Google Scholar]
  38. Pusch S. Krausert S. Fischer V. Balss J. Ott M. Schrimpf D. Capper D. Sahm F. Eisel J. Beck A.C. Jugold M. Eichwald V. Kaulfuss S. Panknin O. Rehwinkel H. Zimmermann K. Hillig R.C. Guenther J. Toschi L. Neuhaus R. Haegebart A. Hess-Stumpp H. Bauser M. Wick W. Unterberg A. Herold-Mende C. Platten M. von Deimling A. Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo. Acta Neuropathol. 2017 133 4 629 644 10.1007/s00401‑017‑1677‑y 28124097
    [Google Scholar]
  39. Ser M.H. Webb M. Thomsen A. Sener U. Isocitrate dehydrogenase inhibitors in glioma: From bench to bedside. Pharmaceuticals 2024 17 6 682 10.3390/ph17060682 38931350
    [Google Scholar]
  40. Popovici-Muller J. Lemieux R.M. Artin E. Saunders J.O. Salituro F.G. Travins J. Cianchetta G. Cai Z. Zhou D. Cui D. Chen P. Straley K. Tobin E. Wang F. David M.D. Penard-Lacronique V. Quivoron C. Saada V. de Botton S. Gross S. Dang L. Yang H. Utley L. Chen Y. Kim H. Jin S. Gu Z. Yao G. Luo Z. Lv X. Fang C. Yan L. Olaharski A. Silverman L. Biller S. Su S.S.M. Yen K. Discovery of AG-120 (Ivosidenib): A first-in-class mutant IDH1 inhibitor for the treatment of IDH1 mutant cancers. ACS Med. Chem. Lett. 2018 9 4 300 305 10.1021/acsmedchemlett.7b00421 29670690
    [Google Scholar]
  41. Liu T. Beck J.P. Hao J. A concise review on hPXR ligand-recognizing residues and structure-based strategies to alleviate hPXR transactivation risk. RSC Med. Chem. 2022 13 2 129 137 10.1039/D1MD00348H 35308029
    [Google Scholar]
  42. Urban D.J. Martinez N.J. Davis M.I. Brimacombe K.R. Cheff D.M. Lee T.D. Henderson M.J. Titus S.A. Pragani R. Rohde J.M. Liu L. Fang Y. Karavadhi S. Shah P. Lee O.W. Wang A. McIver A. Zheng H. Wang X. Xu X. Jadhav A. Simeonov A. Shen M. Boxer M.B. Hall M.D. Assessing inhibitors of mutant isocitrate dehydrogenase using a suite of pre-clinical discovery assays. Sci. Rep. 2017 7 1 12758 10.1038/s41598‑017‑12630‑x 28986582
    [Google Scholar]
  43. Wang F. Travins J. DeLaBarre B. Penard-Lacronique V. Schalm S. Hansen E. Straley K. Kernytsky A. Liu W. Gliser C. Yang H. Gross S. Artin E. Saada V. Mylonas E. Quivoron C. Popovici-Muller J. Saunders J.O. Salituro F.G. Yan S. Murray S. Wei W. Gao Y. Dang L. Dorsch M. Agresta S. Schenkein D.P. Biller S.A. Su S.M. de Botton S. Yen K.E. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013 340 6132 622 626 10.1126/science.1234769 23558173
    [Google Scholar]
  44. Suresh S. Rajvanshi P.K. Noguchi C.T. The many facets of erythropoietin physiologic and metabolic response. Front. Physiol. 2020 10 1534 10.3389/fphys.2019.01534 32038269
    [Google Scholar]
  45. Yen K. Travins J. Wang F. David M.D. Artin E. Straley K. Padyana A. Gross S. DeLaBarre B. Tobin E. Chen Y. Nagaraja R. Choe S. Jin L. Konteatis Z. Cianchetta G. Saunders J.O. Salituro F.G. Quivoron C. Opolon P. Bawa O. Saada V. Paci A. Broutin S. Bernard O.A. de Botton S. Marteyn B.S. Pilichowska M. Xu Y. Fang C. Jiang F. Wei W. Jin S. Silverman L. Liu W. Yang H. Dang L. Dorsch M. Penard-Lacronique V. Biller S.A. Su S.S.M. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 2017 7 5 478 493 10.1158/2159‑8290.CD‑16‑1034 28193778
    [Google Scholar]
  46. Wei A.H. Tiong I.S. Midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and venetoclax bring new hope to AML. Blood 2017 130 23 2469 2474 10.1182/blood‑2017‑08‑784066 29051180
    [Google Scholar]
  47. Piña M.N. Sahu A.K. Frontera A. Biswal H.S. Bauzá A. Tetrel bonds involving a CF3 group participate in protein–drug recognition: a combined crystallographic and computational study. Phys. Chem. Chem. Phys. 2023 25 17 12409 12419 10.1039/D3CP00839H 37093130
    [Google Scholar]
  48. Kim E.S. Enasidenib: First global approval. Drugs 2017 77 15 1705 1711 10.1007/s40265‑017‑0813‑2 28879540
    [Google Scholar]
  49. Dugan J. Pollyea D. Enasidenib for the treatment of acute myeloid leukemia. Expert Rev. Clin. Pharmacol. 2018 11 8 755 760 10.1080/17512433.2018.1477585 29770715
    [Google Scholar]
  50. Wang Z. Zhang Z. Li Y. Sun L. Peng D. Du D. Zhang X. Han L. Zhao L. Lu L. Du H. Yuan S. Zhan M. Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China. Acta Pharm. Sin. B 2021 11 6 1526 1540 10.1016/j.apsb.2021.03.005 34221866
    [Google Scholar]
  51. Zhuang X. Pei H.Z. Li T. Huang J. Guo Y. Zhao Y. Yang M. Zhang D. Chang Z. Zhang Q. Yu L. He C. Zhang L. Pan Y. Chen C. Chen Y. The molecular mechanisms of resistance to idh inhibitors in acute myeloid leukemia. Front. Oncol. 2022 12 931462 10.3389/fonc.2022.931462 35814406
    [Google Scholar]
  52. Stuani L. Sabatier M. Saland E. Cognet G. Poupin N. Bosc C. Castelli F.A. Gales L. Turtoi E. Montersino C. Farge T. Boet E. Broin N. Larrue C. Baran N. Cissé M.Y. Conti M. Loric S. Kaoma T. Hucteau A. Zavoriti A. Sahal A. Mouchel P.L. Gotanègre M. Cassan C. Fernando L. Wang F. Hosseini M. Chu-Van E. Le Cam L. Carroll M. Selak M.A. Vey N. Castellano R. Fenaille F. Turtoi A. Cazals G. Bories P. Gibon Y. Nicolay B. Ronseaux S. Marszalek J.R. Takahashi K. DiNardo C.D. Konopleva M. Pancaldi V. Collette Y. Bellvert F. Jourdan F. Linares L.K. Récher C. Portais J.C. Sarry J.E. Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia. J. Exp. Med. 2021 218 5 e20200924 10.1084/jem.20200924 33760042
    [Google Scholar]
  53. Konteatis Z. Artin E. Nicolay B. Straley K. Padyana A.K. Jin L. Chen Y. Narayaraswamy R. Tong S. Wang F. Zhou D. Cui D. Cai Z. Luo Z. Fang C. Tang H. Lv X. Nagaraja R. Yang H. Su S.S.M. Sui Z. Dang L. Yen K. Popovici-Muller J. Codega P. Campos C. Mellinghoff I.K. Biller S.A. Vorasidenib (AG-881): A first-in-class, brain-penetrant dual inhibitor of mutant IDH1 and 2 for treatment of glioma. ACS Med. Chem. Lett. 2020 11 2 101 107 10.1021/acsmedchemlett.9b00509 32071674
    [Google Scholar]
  54. Carosi F. Broseghini E. Fabbri L. Corradi G. Gili R. Forte V. Roncarati R. Filippini D.M. Ferracin M. Targeting Isocitrate Dehydrogenase (IDH) in solid tumors: Current evidence and future perspectives. Cancers 2024 16 15 2752 10.3390/cancers16152752 39123479
    [Google Scholar]
  55. Lin M.D. Tsai A.C.Y. Abdullah K.G. McBrayer S.K. Shi D.D. Treatment of IDH-mutant glioma in the INDIGO era. NPJ Precis. Oncol. 2024 8 1 149 10.1038/s41698‑024‑00646‑2 39025958
    [Google Scholar]
  56. Open-label study of FT-2102 with or without azacitidine or cytarabine in patients with AML or MDS with an IDH1 mutation NCT02719574 2024
    [Google Scholar]
  57. ASTX727 and FT-2102 in treating IDH1-mutated recurrent/refractory myelodysplastic syndrome or acute myeloid leukemia NCT04013880 2024
    [Google Scholar]
  58. Olutasidenib for the treatment of patients with IDH1 mutated AML, MDS or CMML after donor hematopoietic cell transplant NCT06543381 2024
    [Google Scholar]
  59. Lazarev S. Sindhu K.K. Vorasidenib: A new hope or a false promise for patients with low-grade glioma? Nat. Rev. Clin. Oncol. 2024 21 12 835 836 10.1038/s41571‑024‑00944‑5 39266767
    [Google Scholar]
  60. Sutanto F. Konstantinidou M. Dömling A. Covalent inhibitors: A rational approach to drug discovery. RSC Med. Chem. 2020 11 8 876 884 10.1039/D0MD00154F 33479682
    [Google Scholar]
  61. Singh S. Jain K. Singh J. Garg N. Arora A. FLT3 and IDH1/2 inhibitors for acute myeloid leukemia: Focused clinical narrative review of forthcoming drugs from an Indian Context. Indian J. Med. Paediatr. Oncol. 2024 45 2 115 126 10.1055/s‑0044‑1779621
    [Google Scholar]
  62. Phase I Study of BAY1436032 in IDH1-mutant advanced solid tumors NCT02746081 2024
    [Google Scholar]
  63. Bay1436032 in patients with mutant idh1(midh1) advanced acute myeloid leukemia (aml) NCT03127735 2024
    [Google Scholar]
  64. Safety study of ag-120 or ag-221 in combination with induction and consolidation therapy in participants with newly diagnosed acute myeloid leukemia (aml) with an idh1 and/or idh2 mutation NCT02632708 2024
    [Google Scholar]
  65. A study to assess the safety and efficacy of two combinations of isocitrate dehydrogenase (IDH) mutant targeted therapies plus azacitidine in participants with newly diagnosed acute myeloid leukemia (aml) harboring idh mutations who are not candidates to receive intensive induction chemotherapy NCT02677922 2024
    [Google Scholar]
  66. Ivosidenib and venetoclax with or without azacitidine in treating patients with idh1 mutated hematologic malignancies NCT03471260 2024
    [Google Scholar]
  67. Idh1 (ag 120) inhibitor in patients with idh1 mutated myelodysplastic syndrome NCT03503409 2024
    [Google Scholar]
  68. Idh1 inhibition using ivosidenib as maintenance therapy for idh1-mutant myeloid neoplasms following allogeneic stem cell transplantation NCT03564821 2024
    [Google Scholar]
  69. Ivosidenib (ag-120) with nivolumab in idh1 mutant tumors NCT04056910 2024
    [Google Scholar]
  70. Venetoclax and ivosidenib combined with chemotherapy in idh1 mutated aml (idh1-aml-2024) NCT06611839 2024
    [Google Scholar]
  71. Decitabine/cedazuridine and venetoclax in combination with ivosidenib or enasidenib for the treatment of relapsed or refractory acute myeloid leukemia NCT04774393 2024
    [Google Scholar]
  72. 2024 Ivosidenib + mfolfirinox in patients with resectable pancreatic adenocarcinoma NCT05209074
    [Google Scholar]
  73. Phase 1/2 study of enasidenib (ag-221) in adults with advanced hematologic malignancies with an isocitrate dehydrogenase isoform 2 (idh2) mutation NCT01915498 2024
    [Google Scholar]
  74. Study of orally administered enasidenib (ag-221) in adults with advanced solid tumors, including glioma, or angioimmunoblastic tcell lymphoma, with an idh2 mutation NCT02273739 2024
    [Google Scholar]
  75. An efficacy and safety study of AG-221 (CC-90007) versus conventional care regimens in older subjects with late stage acute myeloid leukemia harboring an isocitrate dehydrogenase 2 mutation (IDHENTIFY) NCT02577406 2024
    [Google Scholar]
  76. Azacitidine and enasidenib in treating patients with IDH2-mutant myelodysplastic syndrome NCT03383575 2024
    [Google Scholar]
  77. IDH2 inhibition using enasidenib as maintenance therapy for IDH2-mutant myeloid neoplasms following allogeneic stem cell transplantation NCT03515512 2024
    [Google Scholar]
  78. A phase 1 study of SH1573 capsules in subjects with refractory or relapsed acute myelogenous leukemia NCT04806659 2024
    [Google Scholar]
  79. A study of vorasidenib in participants with moderate or mild hepatic impairment and matched participants with normal hepatic function NCT05674474 2024
    [Google Scholar]
  80. Study of vorasidenib and pembrolizumab combination in recurrent or progressive IDH-1 mutant glioma NCT05484622 2024
    [Google Scholar]
  81. Study of vorasidenib (AG-881) in participants with residual or recurrent grade 2 glioma with an IDH1 or IDH2 mutation (INDIGO) NCT04164901 2024
    [Google Scholar]
  82. Study of AG-120 and AG-881 in subjects with low grade glioma NCT03343197 2024
    [Google Scholar]
  83. Study of orally administered AG-881 in patients with advanced solid tumors, including gliomas, with an IDH1 and/or IDH2 mutation NCT02481154 2024
    [Google Scholar]
  84. Vorasidenib expanded access program NCT05592743 2024
    [Google Scholar]
  85. Study of oral LY3410738 in patients with advanced hematologic malignancies with IDH1 or IDH2 mutations NCT04603001 2024
    [Google Scholar]
  86. A study to evaluate AG-881 in healthy Japanese and non-Asian participants NCT04145128 2024
    [Google Scholar]
  87. A study to compare the relative bioavailability of two AG-881 formulations and evaluate the effect of food and omeprazole on the pharmacokinetics of AG-881 NCT04128787 2024
    [Google Scholar]
  88. A study to evaluate the effect of AG-881 on the pharmacokinetics of a single dose of lamotrigine in healthy adults NCT04015687 2024
    [Google Scholar]
  89. A safety and pharmacokinetic study of AG-881 in healthy male participants following administration of a single oral dose of [14C] AG-881 and concomitant intravenous microdose of [13C315N3] AG-881 NCT03960502 2024
    [Google Scholar]
  90. Study of orally administered AG-881 in patients with advanced hematologic malignancies with an IDH1 and/or IDH2 mutation NCT02492737 2024
    [Google Scholar]
  91. Study on mass balance of [14C]HMPL-306(isocitrate dehydrogenase inhibitor） in healthy Chinese adult male subjects NCT06671873 2024
    [Google Scholar]
  92. A study to evaluate HMPL-306 in patients with IDH1- and IDH2-mutated acute myeloid leukemia NCT06387069 2024
    [Google Scholar]
  93. A study of HMPL-306 in advanced hematological malignancies with mIDH NCT04764474 2024
    [Google Scholar]
  94. A study of HMPL-306 in advanced solid tumors with IDH mutations NCT04762602 2024
    [Google Scholar]
  95. A study of HMPL-306 in patients with IDH1 and/or IDH2 mutation of relapsed/refractory myeloid leukemia/neoplasms NCT04272957 2024
    [Google Scholar]
  96. A study comparing different formulations of LY3410738 in healthy adult participants NCT06181084 2024
    [Google Scholar]
  97. A study of LY3410738 in healthy adult participants NCT06181045 2024
    [Google Scholar]
  98. Study of the effects of itraconazole and carbamazepine on LY3410738 in healthy participants NCT05205447 2024
    [Google Scholar]
  99. Study of LY3410738 administered to patients with advanced solid tumors with IDH1 or IDH2 mutations NCT04521686 2024
    [Google Scholar]
  100. A clinical study of TQB3454 tablets in the treatment of advanced biliary carcinoma NCT05987358 2024
    [Google Scholar]
  101. A clinical trial of TQB3454 tablets in healthy adult subjects NCT06139367 2024
    [Google Scholar]
  102. A study of TQB3454 tablets in patients with blood tumors NCT06218771 2024
    [Google Scholar]
  103. IDH1 inhibitor AB-218 in patients with advanced IDH1 mutant cholangiocarcinoma and other solid tumor NCT05814536 2024
    [Google Scholar]
  104. Safusidenib phase 2 study in IDH1 mutant glioma NCT05303519 2024
    [Google Scholar]
  105. Phase 2 study of IDH305 in low grade gliomas NCT02987010 2024
    [Google Scholar]
/content/journals/acamc/10.2174/0118715206382095250908095950
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State of the Art of IDH Inhibitors: Emerging Questions and Perspectives
Bentham Science Publishers ; https://doi.org/10.2174/0118715206382095250908095950
/content/journals/acamc/10.2174/0118715206382095250908095950
/content/journals/acamc/10.2174/0118715206382095250908095950
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  • Article Type:     Review Article
Keywords: IDH inhibitors ; IDH mutations ; isocitrate dehydrogenase ; enasidenib ; target therapy ; ivosidenib

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