Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme that catalyzes the oxidative decarboxylation of isocitrate to produce alpha-ketoglutarate (a-KG). Heterozygous mutations in IDH1 at Arg132 cause a neomorphic catalytic activity resulting in the processing of a-KG to R-2-hydroxyglutarate (2-HG), an oncometabolite. 2-HG accumulation in tumors likely interferes with a variety of a-KG dependent enzymes that regulate epigenetic state and cellular differentiation. Therefore, inhibition of 2-HG production with small molecule inhibitors has emerged as a treatment option for patients with IDH1 mutant malignancies. Herein, we describe our efforts to identify potent and selective inhibitors of mutant IDH1. These efforts led to the discovery of IDH305, which demonstrated excellent physicochemical and pharmacological properties suitable for clinical evaluation. IDH305 exhibited robust inhibition of 2-HG production and efficacy in IDH1mut xenograft models. Furthermore, brain exposure of IDH305 was observed in multiple animal models suggesting potential utility in gliomas, which harbor a high frequency of IDH1 mutations. These data support the clinical evaluation of IDH305 across multiple IDH1mut cancers, including AML, solid tumors, and central nervous system malignancies.

Discovery and evaluation of clinical candidate IDH305: A brain penetrant mutant IDH1 inhibitor

254th National Meeting (2017)

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