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
  • 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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