Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers
Janeta Popovici-Muller,Lemieux Rene M,Erin Artin,Jeffrey O. Saunders,Francesco G. Salituro,Jeremy Travins,Giovanni Cianchetta,Zhenwei Cai,Ding Zhou,Cui Dawei,Ping Chen,Kimberly Straley,Erica Tobin,Fang Wang,Muriel D. David,Virginie Penard-Lacronique,Cyril Quivoron,Véronique Saada,Stéphane de Botton,Stefan Gross,Lenny Dang,Hua Yang,Luke Utley,Yue Chen,Hyeryun Kim,Shengfang Jin,Zhiwei Gu,Gui Yao,Zhiyong Luo,Xiaobing Lv,Cheng Fang,Liping Yan,Andrew J. Olaharski,Lee Silverman,Scott A. Biller,Shinsan M. Su,Katharine E. Yen +36 more
TLDR
AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo is reported.Abstract:
Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.read more
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Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML
Courtney D. DiNardo,Eytan M. Stein,S. de Botton,Gail J. Roboz,Jessica K. Altman,Alice S. Mims,Ronan T. Swords,Robert H. Collins,Gabriel N. Mannis,Daniel A. Pollyea,William B. Donnellan,Amir T. Fathi,A. Pigneux,Harry P. Erba,Gabrielle T. Prince,Anthony S. Stein,Geoffrey L. Uy,James M. Foran,Elie Traer,Robert K. Stuart,Martha Arellano,James L. Slack,Mikkael A. Sekeres,Christophe Willekens,Sung Choe,Hongfang Wang,Vickie Zhang,Katharine E. Yen,Stephanie M. Kapsalis,Hua Yang,David Dai,Bin Fan,Meredith Goldwasser,Hua Liu,Samuel V. Agresta,Bin Wu,Eyal C. Attar,Martin S. Tallman,Richard Stone,Hagop M. Kantarjian +39 more
TL;DR: In patients with advanced IDH1‐mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment‐related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission.
Journal ArticleDOI
Oxidative Stress in Cancer.
TL;DR: During progression and metastasis, tumor cells adapt to oxidative stress by increasing NADPH in various ways, including activation of AMPK, the PPP, and reductive glutamine and folate metabolism.
Journal ArticleDOI
Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study
Ghassan K. Abou-Alfa,Ghassan K. Abou-Alfa,Teresa Macarulla,Milind Javle,Robin Kate Kelley,Sam J. Lubner,Jorge Adeva,James M. Cleary,Daniel V.T. Catenacci,Mitesh J. Borad,John Bridgewater,William P. Harris,Adrian Murphy,Do Youn Oh,Jonathan R. Whisenant,Maeve A. Lowery,Lipika Goyal,Rachna T. Shroff,Anthony B. El-Khoueiry,Bin Fan,Bin Wu,Christina X. Chamberlain,Liewen Jiang,Camelia Gliser,Shuchi Sumant Pandya,Juan W. Valle,Andrew X. Zhu,Andrew X. Zhu +27 more
TL;DR: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivOSidenib was well tolerated, and this study shows the clinical benefit of targeting IDH1 mutations in advanced,IDH1-mutant cholangiocarcinoma.
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Small molecules in targeted cancer therapy: advances, challenges, and future perspectives.
Lei Zhong,Y. Li,Liang Xiong,Wen-Jing Wang,Ming Wu,Ting Yuan,Wei Yang,Chenyu Tian,Zhuang Miao,Tianqi Wang,Shengyong Yang +10 more
TL;DR: A comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification is conducted, which presents all the approved drugs as well as important drug candidates in clinical trials for each target, and discusses the current challenges.
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Navigating metabolic pathways to enhance antitumour immunity and immunotherapy
Xiaoyun Li,Mathias Wenes,Pedro Romero,Stanley Ching-Cheng Huang,Sarah-Maria Fendt,Sarah-Maria Fendt,Ping-Chih Ho +6 more
TL;DR: An overview of the pathways of cancer metabolism that intersect with immunometabolism, typically resulting in immunosuppression, is provided, with a focus on how these metabolic pathways could be targeted in order to enhance anticancer immunity and immunotherapy.
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Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Lenny Dang,David W. White,Stefan Gross,Bryson D. Bennett,Mark A. Bittinger,Edward M. Driggers,Valeria Fantin,Hyun Gyung Jang,Shengfang Jin,Marie C. Keenan,Kevin Marks,Robert M. Prins,Patrick S. Ward,Katharine E. Yen,Linda M. Liau,Joshua D. Rabinowitz,Lewis C. Cantley,Craig B. Thompson,Matthew G. Vander Heiden,Matthew G. Vander Heiden,Shinsan M. Su +20 more
TL;DR: It is shown that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG), and that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
Journal ArticleDOI
Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation.
Maria E. Figueroa,Omar Abdel-Wahab,Chao Lu,Patrick S. Ward,Jay P. Patel,Alan Shih,Yushan Li,Neha Bhagwat,Aparna Vasanthakumar,Hugo F. Fernandez,Martin S. Tallman,Zhuoxin Sun,Kristy L. Wolniak,Justine K. Peeters,Wei Liu,Sung E. Choe,Valeria Fantin,Elisabeth Paietta,Bob Löwenberg,Jonathan D. Licht,Lucy A. Godley,Ruud Delwel,Peter J. M. Valk,Craig B. Thompson,Ross L. Levine,Ari Melnick +25 more
TL;DR: Mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specificHypermethylation signature, suggesting a shared proleukemogenic effect.
Journal ArticleDOI
IDH mutation impairs histone demethylation and results in a block to cell differentiation
Chao Lu,Patrick S. Ward,Patrick S. Ward,Gurpreet S. Kapoor,Dan Rohle,Dan Rohle,Sevin Turcan,Omar Abdel-Wahab,Christopher R. Edwards,Raya Khanin,Maria E. Figueroa,Ari Melnick,Kathryn E. Wellen,Donald M. O'Rourke,Shelley L. Berger,Timothy A. Chan,Ross L. Levine,Ingo K. Mellinghoff,Ingo K. Mellinghoff,Craig B. Thompson +19 more
TL;DR: It is reported that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells, and that inhibition of histone methylation can be sufficient to block the differentiation of non-transformed cells.
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