VER-246808

VER-246808 is a small molecule inhibitor of pyruvate dehydrogenase kinase (PDHK) developed by Vernalis, a subsidiary of Servier. PDHK is a mitochondrial enzyme that phosphorylates and inactivates the pyruvate dehydrogenase complex (PDC), a key gatekeeper that links glycolysis to the tricarboxylic acid (TCA) cycle. In many cancer types, PDHK is overexpressed, leading to the suppression of mitochondrial oxidative phosphorylation and a shift toward aerobic glycolysis (the Warburg effect), which supports rapid tumor growth and survival. By inhibiting PDHK, VER-246808 restores PDC activity, promoting the oxidation of pyruvate in the mitochondria, increasing reactive oxygen species (ROS) levels, and potentially inducing apoptosis in cancer cells. The compound was identified using fragment-based drug discovery (FBDD) and is currently in preclinical development for the treatment of various cancers.