Human dihydroorotate dehydrogenase (hDHODH) is an enzyme that catalyzes the fourth step in de novo pyrimidine biosynthesis, and its inhibitors restrict the growth of rapidly proliferating cells. Therefore, hDHODH has been reported as an attractive target for the treatment of cancer and autoimmune diseases. In this study, several quinoline derivatives were identified as potent inhibitors against hDHODH, among which compound A9 was the most potent one with an IC₅₀ value of 9.7 nM. We further verified that A9 could directly bind to the target hDHODH by thermal shift assay (TSA), surface plasmon resonance (SPR) and X-ray crystallography. Moreover, the binding mode of compound A9 and structure-activity relationship (SAR) of quinoline derivatives with hDHODH were summarized.

Med. Chem. Commun., 2016, 7, 853

DOI: 10.1039/c6md00024j