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

Area of Science:

• Oncology
• Medicinal Chemistry
• Biochemistry

Background:

• Mutant isocitrate dehydrogenase 1 (IDH1) is a key driver in over 70% of grade II/III gliomas and ~10% of acute myeloid leukemia (AML).
• IDH1 mutations result in the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG), promoting tumor growth.

Purpose of the Study:

• To develop a potent, selective, orally bioavailable, and brain-penetrant inhibitor for mutant IDH1.
• To address and minimize glutathione S-conjugate (GSH-adduct) formation observed during in vitro metabolism studies of early drug candidates.

Main Methods:

• Design and synthesis of a novel tricyclic diazepine scaffold targeting mutant IDH1.
• Systematic modification of the tricyclic core to reduce its electron-rich nature and block metabolic hotspots.
• Evaluation of in vitro metabolism, including GSH-adduct formation across species.
• Assessment of overall drug profile including potency, selectivity, and pharmacokinetic properties.

Main Results:

• Identification of a potent, selective, and orally bioavailable brain-penetrant tricyclic diazepine inhibitor of mutant IDH1.
• Development of core modifications and substitution pattern changes (C8 N → C linked) significantly reduced GSH-adduct formation.
• New analogues demonstrated minimal GSH-adduct formation across tested species while maintaining a balanced pharmacological profile.

Conclusions:

• Chemical modifications to the tricyclic core effectively mitigated metabolic liabilities, specifically GSH-adduct formation.
• The optimized analogues represent promising drug candidates for treating IDH1-mutated cancers.
• This work highlights a successful strategy for improving the metabolic stability and safety profile of drug candidates targeting mutant IDH1.