Mutant IDH1-IN-6 is an orally active compound that effectively inhibits mutant isocitrate dehydrogenase (IDH) enzymes. It demonstrates potency and selectivity, with IC50 values of 6.27, 3.71, 36.9, and 11.5 nM for IDH1 R132H, IDH1 R132C, IDH2 R140Q, and IDH2 R172K mutants, respectively. Notably, Mutant IDH1-IN-6 exhibits lower activity in inhibiting wild-type IDH enzymes.

IDH2 (R172K):11.5 nM (IC50), IDH1 (R132C):3.71 nM (IC50), IDH2 (R140Q):36.9 nM (IC50), IDH1 (R132H):6.27 nM (IC50), IDH2 (WT):884 nM (IC50), IDH1 (WT):105 nM (IC50)

Mutant IDH1-IN-6 (example 2) selectively inhibits 2-hydroxyglutarate production in HT1080 cells by targeting mutant IDH1 R132C with an IC50 of 1.28 nM, without affecting aKG production by wild-type IDH1, demonstrating its specificity for mutant IDH1 in cellular environments[1].

Treatment with Mutant IDH1-IN-6 (Example 2; 0-32 mg/kg; oral gavage; twice daily for 3 days) hampers the production of 2-hydroxyglutarate in a dose-responsive manner in IDH1 mutant xenograft mice [1]. The study utilized athymic nude mice (20-22 g), which were administered TB08 cells, exploring dosage levels ranging from 1 mg/kg to 32 mg/kg. The regimen involved oral gavage administered twice daily over a period of three days, resulting in the inhibition of 2-hydroxyglutarate in IDH1 mutant xenograft mice.