AGI-5198

AGI-5168 was the prototypical IDH-1 R132H inhibitor but in time has been surpassed in potency and characterization by the later compound GSK864, which also offers an inactive control for proof of target involvement. However, as a second, distinct chemotype this probe may offer some utility for confirmation of phenotypes in cellular assays.

AGI-5198 is a potent, selective inhibitor of IDH1 R132H and R132C mutants [in vitro IC50 R132H IDH1 = 0.07 µM and IC50 R132C IDH1 = 0.16 µM, respectively]. The compound is totally selective against wild-type IDH1, wild-type IDH2 or IDH2 mutants (IC50s > 100 μM). Compared in a R132H-IDH1 glioma xenografts, AGI-5198 (450 mg/kg/day) caused 50-60% growth inhibition over a treatment period of three weeks (no sign of toxicity during 3 weeks daily treatment). AGI-5198 did not affect the growth of IDH1 wild-type glioma xenograph. In the U87 R132H tumor xenograft mouse model, AGI-5198 shows ∼90% tumor 2-HG inhibition in vivo following three twice daily doses (150 mg/kg).

AGI-5198 has been superseded in biochemical and cellular potency by GSK864 and is recommended mainly for use as a mutant IDH1 inhibitor from a distinct chemical class for confirmatory studies in cells. Characterization of off-target activities in cells would be helpful to support use of this compound. AGI-5198 requires high doses for in vivo activity, but the oral dosing route may be of use, compared to GSK864 which is recommended for intraperitoneal dosing.