Dihydroorotate dehydrogenase (DHODH) is a highly conserved enzyme. All organisms express it. Class-1 DHODHs are cytoplasmic and single-domain enzymes. Conversely, class-2 DHODHs are membrane-associated and two-domain enzymes. Both classes of DHODHs use FMN to oxidize DHODH. To regenerate FMN, class-1 enzymes use a soluble cofactor, such as NAD+ or fumarate, that binds close to FMNH2. Class-2 enzymes use ubiquinone (CoQ) as the oxidant. CoQ binds in a hydrophobic region of the N-terminal domain. But, it does not contain an FMN-binding site. hDHODH is a flavin-dependent mitochondrial enzyme. It has relevance in de novo pyrimidine biosynthesis. It is a validated therapeutic target for the treatment of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. However, human DHODH inhibitors become a target to treat for cancer, parasite infections (i.e. malaria) and viruses as well as in the agrochemicals industry. ASLAN003 is an orally active and potent inhibitor of DHODH.
ASLAN003 has the potential to be a first-in-class candidate in acute myelogenous leukemia (AML) and exhibits antitumor activity.
AML is a clinically devastating disease with a dismal prognosis and survival rate. Efforts to identify new therapeutic targets to overcome myeloid differentiation blockade are mostly unsuccessful. However, the inhibition of hDHODH enables myeloid differentiation in both human and mouse AML models. These findings have significantly increased the interest in hDHODH-targeted therapy for cancer. In particular, they are a potential new strategy for the treatment of AML.
All in all, hDHODH is a new target on AML. ASLAN003 is an orally active and potent inhibitor of hDHODH with antitumor activity. Thus, it has the potential to be a first-in-class candidate in AML.
Reference:
Shih KC, et al. PLoS One. 2014 Feb 4;9(2):e87960.