Discovery of Nanomolar Inhibitors for Human Dihydroorotate Dehydrogenase Using Structure-Based Drug Discovery Methods

We used a structure-based drug discovery approach to identify novel inhibitors of human Dihydroorotate Dehydrogenase (DHODH), which is a therapeutic target for treating Cancer and autoimmune and inflammatory diseases. In the case of acute myeloid leukemia, no previously discovered DHODH inhibitors have yet succeeded in this clinical application. Thus, there remains a strong need for new inhibitors that could be used as alternatives to the current standard-of-care. Our goal was to identify novel inhibitors of DHODH. We implemented prefiltering steps to omit PAINS and Lipinski violators at the earliest stages of this project. This enriched compounds in the data set that had a higher potential of favorable oral druggability. Guided by Glide SP docking scores, we found 20 structurally unique compounds from the ChemBridge EXPRESS-pick library that inhibited DHODH with IC_{50, DHODH} values between 91 nM and 2.7 μM. Ten of these compounds reduced MOLM-13 cell viability with IC_{50, MOLM-13} values between 2.3 and 50.6 μM. Compound 16 (IC_{50, DHODH} = 91 nM) inhibited DHODH more potently than the known DHODH inhibitor, teriflunomide (IC_{50, DHODH} = 130 nM), during biochemical characterizations and presented a promising scaffold for future hit-to-lead optimization efforts. Compound 17 (IC_{50, MOLM-13} = 2.3 μM) was most successful at reducing survival in MOLM-13 cell lines compared with our other hits. The discovered compounds represent excellent starting points for the development and optimization of novel DHODH inhibitors.