Olutasidenib is a potent, orally bioavailable, brain penetrant and selective mutant IDH1 (mIDH1) inhibitor with IC50 of 21.1 nM, 114 nM for IDH1-R132H, IDH1-R132C, respectively.
Olutasidenib (FT-2102) Olutasidenib is a potent, orally bioavailable, brain penetrant and selective mutant IDH1 (mIDH1) inhibitor with IC50 of 21.1 nM, 114 nM for IDH1-R132H , IDH1-R132C , respectively.
Profiling in various mIDH1 over-expressing U87 cells and HCT116 cells reveals that olutasidenib potently inhibits 2-HG production by multiple IDH1-R132 mutants (R132H, R132C, R132G, R132L), suggesting olutasidenib could be efficacious against most IDH1-R132 mutant-expressing tumors. Olutasidenib is highly selective for IDH1 isoforms, showing no appreciable inhibition against wild-type IDH1 and IDH2 mutants..
In vivo
In IDH1-R132H/ xenograft models, the free concentration of Olutasidenib is comparable in plasma and xenograft tumors, and exposures are dose-dependent. In comparison to the vehicle treated group, Olutasidenib shows a time and dose-dependent inhibition of 2-HG levels in tumor. Calculations based upon the percentage of suppression of 2-HG concentration in tumor versus the free drug concentration in tumor give in vivo IC50 values of 26 nM and 36 nM in the HCT116-IDH1-R132H or HCT116-IDH1-R132C models, respectively. Olutasidenib has good cell permeability and low efflux ratio in the male CD-1 mouse, which indicate a low probability of p-glycoprotein driven efflux..
1.Wang G, Sai K, Gong F, Yang Q, Chen F, Lin J. (2014) Mutation of isocitrate dehydrogenase 1 induces glioma cell proliferation via nuclear factor-κB activation in a hypoxia-inducible factor 1-α dependent manner.. Mol Med Rep, 9 (5):(1799-805). [PMID:24626950][10.1021/op500134e]
2.Caravella JA, Lin J, Diebold RB, Campbell AM, Ericsson A, Gustafson G, Wang Z, Castro J, Clarke A, Gotur D et al.. (2020) Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor.. J Med Chem, 63 (4):(1612-1623). [PMID:31971798][10.1021/op500134e]
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