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. 2022 Mar 28;13(4):734-741.
doi: 10.1021/acsmedchemlett.2c00089. eCollection 2022 Apr 14.

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

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

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

Chunhui Huang et al. ACS Med Chem Lett. .

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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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Representative molecules of the tricyclic diazepine series. MOG cell-based assay was run using engineered wild-type IDH1 glioma cell line MOG-G-UVW to express mutant IDH1 R132H protein. *Time-dependent inhibition (TDI) of CYP3A4, wherein an IC50 shift >1 (the ratio between IC50 values in the absence vs presence of NADPH) is considered a TDI risk.
Scheme 1
Scheme 1. Major Metabolites of 2 in Rat Hepatocytes
Figure 2
Figure 2
Site of metabolism prediction of 1 by MetaSite.
Figure 3
Figure 3
P-gp BA/AB ratio analysis of 15 matched pairs with structure difference at C3 only (with or without fluorine substituent). C3-F substituted compounds are shown in green cycles, and C3 unsubstituted analogues are shown in red cycles.
Figure 4
Figure 4
Ar–Br intermediate 19 showed low GSH-adduct formation.
Figure 5
Figure 5
Relationship between oxidation half-wave potential (E1/2) measured by coulometric electrochemistry and %GSH-adducts in RLM. Red squares, N-linked compounds including core modifications (F-substitutions and aza-cores) [higher risk]; green circles, C-linked analogues [lower risk]. See Supporting Information, Table S2 for details.
See this image and copyright information in PMC

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