DHODH inhibitors and leukemia: an emergent interest for new myeloid differentiation agents

Human dihydroorotate dehydrogenase (hDHODH, EC 1.3.99.11) is a flavin-dependent enzyme of the inner mitochondrial membrane that catalyzes the conversion of dihydroorotate to orotate, which is the only redox step in the de novo pyrimidine biocascade. From a pharmacological point of view, hDHODH has already been validated as a therapeutic target for the treatment of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. However, in the fall of 2016, hDHODH inhibitors were discovered to induce in vivo myeloid differentiation, and thus a completely new opportunity, that of treating acute myeloid leukemia (AML), came to the fore. Pharmaceutical companies and academic groups have invested in the design of new hDHODH inhibitors since that moment. This review focuses on the latest advances in the development and application of hDHODH inhibitors in the AML field. After a brief overview of AML treatment options, this review will analyze the importance of myeloid differentiation and its connection with hDHODH. Subsequently, it will provide a detailed description of the ongoing drug design programs in the area and, finally, an updated classification of currently available hDHODH inhibitors will be presented.