Definition

An orally available inhibitor of dihydroorotate dehydrogenase (DHODH), with potential antineoplastic activity. Upon oral administration, DHODH inhibitor JNJ-74856665 specifically targets and binds to DHODH’s ubiquinone binding site, thereby preventing the activation of DHODH. This prevents the fourth enzymatic step in de novo pyrimidine synthesis. This prevents uridine monophosphate (UMP) formation, DNA synthesis, cell division and cellular proliferation, causes reactive oxygen species (ROS) formation, enables differentiation, causes cell cycle arrest and induces apoptosis in susceptible tumor cells. DHODH, a mitochondrial enzyme, catalyzes the conversion of dihydroorotate (DHO) to orotate in the endogenous synthesis of UMP.