ML-390 is an inhibitor of dihydroorotate dehydrogenase (DHODH), the enzyme that converts dihydroorotate to orotate during de novo pyrimidine synthesis. In acute myeloid leukemia, leukemic myeloblast development is halted at an immature stage leading to perpetual self-renewal rather than differentiation. ML-390 induces differentiation in the acute myeloid leukemia cell lines U937 (murine) and THP-1 (human) cell lines with an EC50 value of approximately 2 μM.
in the screening study, ml390 was identified as the most potent compound against the engineered erhox-gfp cell line. moreover, the addition of uridine to the cell culture media could abrogate the differentiation effects of ml390, demonstrating further evidences that ml390’ effects were due to their inhibition of dhodh-catalyzed pyrimidine synthesis. in addition, ml390 was found to be not able to inhibit dhodh in the p. falciparum parasite, which is the causative agent of malaria. furthermore, the x-ray structure indicated that the binding of ml390 to the enzyme might be increased by modifying ml390 with a ring in its central portion to lock the molecule into its binding conformation with the amide substituents [1].
