Crelosidenib is a potent and selective mutant IDH inhibitor with IC50s of 6.27 nM, 3.71 nM, 36.9 nM, and 11.5 nM for IDH1 R132H, IDH1 R132C, IDH2 R140Q, and IDH2 R172K mutases, respectively, and low inhibitory activity against the wild-type IDH enzyme.

HT1080 cells:1.28 nM

Crelosidenib (Example 2) suppresses 2-hydroxyglutarate production in HT1080 cells with an IC₅₀ of 1.28 nM, demonstrating effective inhibition of mutant IDH1 R132C activity in a cellular context. The level of α-ketoglutarate (aKG), a product of wild-type IDH1, remains unchanged, confirming the compound’s selectivity for the mutant enzyme over the wild-type form[1].

Treatment with Crelosidenib (Example 2) via oral gavage at doses ranging from 0 to 32 mg/kg, administered twice daily for 3 days, resulted in a dose-dependent reduction of 2-hydroxyglutarate levels in xenograft mice bearing IDH1 mutations[1].