ML309: A potent inhibitor of R132H mutant IDH1 capable of reducing 2-hydroxyglutarate production in U87 MG glioblastoma cells

The emergence of the role of isocitrate dehydrogenase (IDH) in cancer resulted from genomic sequencing for 22 glioma genomes that found recurrent mutation of IDH1 on chromosome 2q33. Subsequent sequencing of over 900 tumors revealed recurrent IDH mutations in both IDH1 and IDH2 in up to 70% of secondary gliomas and in ~16–17% of acute myeloid leukemia (AML) cases. The mutated residue in IDH1 is most commonly arginine 132, which is most often replaced with either histidine or cysteine. This active site mutation results in loss of activity for metabolism of isocitrate, but confers gain-of-function for the production of the oncometabolite 2-hydroxyglutarate (2-HG). Herein we describe the quantitative high throughput screening of the R132H mutant IDH1 enzyme and the subsequent medicinal chemistry optimization of the small molecule hit. The resulting probe, ML309, is capable of potent and selective inhibition of mutant IDH1 and effectively lowers cell-based production of 2-HG in a U87MG mutant glioblastoma cell line. We hope that this probe leads to important studies into the role of IDH1 as an oncogene, 2HG as an oncometabolite, and can potentially provide opportunities to discover much needed therapies for glioma and AML patients in the future.