CyanoPyridine Scaffolds Selected :
Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers
Janeta Popovici-Muller†∇, René M. Lemieux†⊥, Erin Artin†⊥, Jeffrey O. Saunders†#, Francesco G. Salituro†▲ 
, Jeremy Travins†□, Giovanni Cianchetta†, Zhenwei Cai‡, Ding Zhou‡⊗, Dawei Cui‡, 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 Olaharski†+, Lee Silverman†, Scott Biller†, Shin-San M. Su†∇, and Katharine Yen*†
, Jeremy Travins†□, Giovanni Cianchetta†, Zhenwei Cai‡, Ding Zhou‡⊗, Dawei Cui‡, 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 Olaharski†+, Lee Silverman†, Scott Biller†, Shin-San M. Su†∇, and Katharine Yen*†
† Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States
‡ PharmaResources, Shanghai 201201, China
§ ChemPartner, Shanghai 201203, China
∥ INSERM U1170 and Gustave Roussy, Villejuif 94800, France
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.7b00421
Publication Date (Web): January 19, 2018
Copyright © 2018 American Chemical Society
*E-mail: katharine.yen@agios.com.
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.
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.7b00421.
- Synthesis and profiling of AG-120, experimental procedures, synthetic details and characterization of compounds, and abbreviations (PDF)
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