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ID: ALA5046317
Journal: ACS Med Chem Lett
Title: Diminishing GSH-Adduct Formation of Tricyclic Diazepine-based Mutant IDH1 Inhibitors.
Authors: Huang C, Fischer C, Machacek MR, Bogen S, Biftu T, Huang X, Reutershan MH, Otte R, Hong Q, Wu Z, Yu Y, Park M, Chen L, Biju P, Knemeyer I, Lu P, Kochansky CJ, Hicks MB, Liu Y, Helmy R, Fradera X, Donofrio A, Close J, Maddess ML, White C, Sloman DL, Sciammetta N, Lu J, Gibeau C, Simov V, Zhang H, Fuller P, Witter D.
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.
CiteXplore: 35450359