IDH889 is an Orally Available and Mutant Specific IDH1 Inhibitor

Heterozygous mutations in human cytoplasmic isocitrate dehydrogenase 1 (IDH1) at Arg¹³² (R132) occur in multiple cancer types, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma. In this study, Julian R. Levell, et al identified IDH889, which is a potent inhibitor of IDH1^R132H by high throughput screening. Especially, IDH889 binds into an allosteric, induced-fit pocket in IDH1^R132H. Moreover, IDH889 has good overall selectivity vs the wild-type protein, and inhibits both the IDH1^R132H and IDH1R132C mutants. Furthermore, IDH889 has broad utility across the various known R132 mutations. IDH889 also has excellent permeability and no efflux in the Caco-2 and human MDR1-MDCK cell lines.

IDH889 can penetrate the blood-brain barrier. To assess brain/plasma ratio of IDH889 in a rat pharmacokinetics study, researchers demonstrate favorable distribution to the brain of IDH889. The result is 30 mg/kg po with the 1.4 brain/blood ratio. IDH889 also demonstrates significantly improved plasma exposure in mice vs IDH662 (AUC 3.6 μM•h, C_max 1.7 μM at 10 mg/kg; AUC 55.5 μM•h, C_max 14.2 μM at 100 mg/kg). To illustrate, researchers optimized the high throughput screening hit for potency and PK properties to generate IDH889 suitable for exploring the effect of inhibition of production of 2-HG by IDH1^R132H in vitro and in vivo cancer models. Oral dosing of IDH889 in a murine IDH1 mutant tumor xenograft model shows robust reduction of tumor derived 2-HG, a PD biomarker of mutant-IDH1^R132 activity.

In conclusion, IDH889 is a potent inhibitor of IDH1^R132 for treating patients with IDH1 mutant brain cancers.

Reference:
Levell JR, et al. Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1. ACS Med Chem Lett. 2016 Dec 16;8(2):151-156.