DHODH inhibitor JBZ-001

An orally available inhibitor of dihydroorotate dehydrogenase (DHODH), with potential antineoplastic, activity. Upon oral administration, DHODH inhibitor JBZ-001 specifically targets, binds to and prevents the activation of DHODH, thereby preventing the fourth enzymatic step in de novo pyrimidine synthesis. This causes metabolic stress and prevents uridine monophosphate (UMP) formation, DNA synthesis, cell division and cellular proliferation, promotes cell differentiation, causes cell cycle arrest and induces apoptosis in susceptible tumor cells. Specifically, JBZ-001 induces the differentiation of immature myeloid cells and driving them toward a more mature, functional state as seen in morphological changes in acute myeloid leukemia (AML) cells. In addition, JBZ-001 induces the upregulation of CD38 and CD47 on susceptible cancer cells, thereby improving efficacy of CD38- and CD47-targeted therapies. DHODH, a mitochondrial enzyme, catalyzes the conversion of dihydroorotate (DHO) to orotate in the endogenous synthesis of UMP.