Ulanet, Danielle, Chubukov, Victor, Coco, John, McDonald, Gabrielle, Steadman, Mya, Narayanaswamy, Rohini, Ronseaux, Sebastien, Choe, Sung, Erdmann, Tabea, Truskowski, Kevin, Nellore, Kavitha, Rao, Siva Sanjeeva, Subramanya, Hosahalli, Lenz, Georg, Cooper, Michael, Murtie, Josh, and Marks, Kevin
Rapidly proliferating cells reprogram metabolism to support increased biosynthetic demands, a feature that can expose targetable vulnerabilities for therapeutic intervention. A chemical biology screen was performed in an effort to identify metabolic vulnerabilities in particular tumor subtypes, and revealed potent and selective activity of a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic origin. In contrast, cancer cell lines of solid tumor origin exhibited comparatively poor sensitivity. Evaluation of a lymphoma cell line panel demonstrated broad responsiveness to DHODH inhibition, independent of clinical subtype (e.g. ABC, GCB, double-hit).