DS-1001b

DS-1001b is an inhibitor of mutant isocitrate dehydrogenase 1 (IDH1; IC₅₀s = 15 and 130 nM for IDH1^R132H and IDH1^R132C, respectively).¹ It is selective for mutant IDH1, which converts α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), over wild-type IDH1 and IDH2, which convert isocitrate to α-ketoglutarate, as well as IDH2^R140Q and IDH2^R172Q (IC₅₀s = >10,000 nM for all). DS-1001b inhibits 2-HG production in TF-1 cells stably transfected with IDH1^R132H or IDH1^R132C (IC₅₀s = 29 and 35 nM, respectively) and in 293A cells transiently transfected with IDH1^R132H or IDH1^R132C (IC₅₀s = 29 and 42 nM, respectively). DS-1001b reduces tumor growth, as well as intratumoral and plasma 2-HG levels, in a subcutaneous IDH1^R132H-expressing A1074 patient-derived xenograft (PDX) mouse model of glioblastoma.

1.Machida, Y., Nakagawa, M., Matsunaga, H., et al.A potent blood-brain barrier-permeable mutant IDH1 inhibitor suppresses the growth of glioblastoma with IDH1 mutation in a patient-derived orthotopic xenograft modelMol. Cancer Ther.19(2)375-383(2020)