Olutasidenib

Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor used to treat patients with acute myeloid leukemia (AML) and IDH1 genetic mutations associated with cancer development. IDH1 catalyzes the oxidative decarboxylation of isocitrate to form α-ketoglutarate (α-KG). However, mutations in IDH1 occur in the active catalytic sites of the arginine residues and promote the conversion of α-KG to 2-hydroxyglutarate (2-HG), an oncometabolite that leads to the formation of tumors. This causes an increase in 2-HG levels, inhibiting α-KG-dependent mechanisms, such as epigenetic regulation, collagen synthesis and cell signaling. IDH1 mutations have been detected in different types of cancers, including AML, and some of the most common IDH1 mutations in patients with AML are R132H and R132C substitutions.

Olutasidenib acts as a selective IDH1 inhibitor with affinity only towards the mutated enzyme. In vitro studies have shown that olutasidenib inhibits mutated IDH1 R132H, R132L, R132S, R132G, and R132C proteins, but not wild-type IDH1 or mutated IDH2 proteins. Through the inhibition of mutant IDH1, olutasidenib reduces 2-HG levels, which promotes the restoration of normal cellular differentiation and provides a therapeutic benefit in IDH1-mutated cancers.