Definition

An orally bioavailable inhibitor of mitochondrial enzyme isocitrate dehydrogenase type 2 (IDH2; IDH-2) R140Q mutant, with potential antineoplastic activity. Upon oral administration, IDH2 mutant inhibitor SH1573 specifically inhibits mutant IDH2 (mIDH2) R140Q protein, thereby inhibiting the formation of the oncometabolite 2-hydroxyglutarate (2HG) from alpha-ketoglutarate (a-KG). This prevents 2HG-mediated signaling and leads to both an induction of cellular differentiation and an inhibition of cellular proliferation in tumor cells expressing mIDH2 R140Q. IDH2 is mutated in a variety of cancers, and mutated IDH2 initiates and drives cancer growth by catalyzing the formation of 2HG and blocking cell differentiation.