2. Academic Validation
  3. Diminishing GSH-Adduct Formation of Tricyclic Diazepine-based Mutant IDH1 Inhibitors

Diminishing GSH-Adduct Formation of Tricyclic Diazepine-based Mutant IDH1 Inhibitors

  • ACS Med Chem Lett. 2022 Mar 28;13(4):734-741. doi: 10.1021/acsmedchemlett.2c00089.
Chunhui Huang 1,  Christian Fischer 1,  Michelle R Machacek 1,  Stephane Bogen 2,  Tesfaye Biftu 2,  Xianhai Huang 2,  Michael H Reutershan 1,  Ryan Otte 1,  Qingmei Hong 2,  Zhicai Wu 2,  Yang Yu 2,  Min Park 2,  Lei Chen 2,  Purakkattle Biju 2,  Ian Knemeyer 3,  Ping Lu 3,  Christopher J Kochansky 3,  Michael Brendan Hicks 4,  Yong Liu 4,  Roy Helmy 4,  Xavier Fradera 1,  Anthony Donofrio 1,  Josh Close 1,  Matthew L Maddess 1,  Catherine White 1,  David L Sloman 1,  Nunzio Sciammetta 1,  Jun Lu 3,  Craig Gibeau 1,  Vladimir Simov 1,  Hongjun Zhang 1,  Peter Fuller 1,  David Witter 1
Affiliations

Affiliations

  • 1 Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • 2 Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
  • 3 Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 4 Merck & Co., Inc., Rahway, New Jersey 07065 United States.
PMID: 35450359 DOI: 10.1021/acsmedchemlett.2c00089
Abstract

Mutant isocitrate dehydrogenase 1 (IDH1) has been identified as an attractive oncology target for which >70% of grade II and III gliomas and ∼10% of acute myeloid leukemia (AML) harbor somatic IDH1 mutations. These mutations confer a neomorphic gain of function, leading to the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). We identified and developed a potent, selective, and orally bioavailable brain-penetrant tricyclic diazepine scaffold that inhibits mutant IDH1. During the course of in vitro metabolism studies, GSH-adduct metabolites were observed. The hypothesis for GSH-adduct formation was driven by the electron-rich nature of the tricyclic core. Herein, we describe our efforts to reduce the electron-rich nature of the core. Ultimately, a strategy focused on core modifications to block metabolic hot spots coupled with substitution pattern changes (C8 N → C linked) led to the identification of new tricyclic analogues with minimal GSH-adduct formation across species while maintaining an overall balanced profile.

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