Dihydroorotate dehydrogenase (DHODH), located in the inner membrane of mitochondria, is an iron-containing flavin-dependent enzyme. Using the cofactor ubiquinone, DHODH catalyzes the fourth step in the de novo biosynthesis of pyrimidine by converting dihydroorotate into orotate in a redox reaction in the mitochondria. DHODH is the only enzyme capable of performing this conversion. Therefore, it is essential for the cell’s ability to produce uridine monophosphate. It is originally a target for the treatment of the non-neoplastic diseases involving in rheumatoid arthritis and multiple sclerosis, and is re-emerging as a validated therapeutic target for cancer therapy.
UMP is the first building block in the production of pyrimidine ribonucleosides and deoxyribonuclesides for RNA and DNA synthesis, respectively. Pyrimidine nucleotides play a significant role in tumor cell proliferation as precursors of RNA and DNA. Inhibitors of DHODH function by blocking this proximal step leading to the rapid depletion of UMP, UDP, and UTP. Moreover, small molecule inhibitors of DHODH are highly effective in vitro and in vivo in pre-clinical models of malignancy.
Brequinar (DUP785), a potent inhibitor of DHODH, has potent activities against a broad spectrum of viruses.
Brequinar (DuP-785) is a potent and selective inhibitor of the enzyme DHODH. It blocks synthesis of pyrimidine based nucleotides in the body and so inhibits cell growth. It is also an immunosuppressant for preventing rejection after organ transplant and also as an anti-cancer drug. What’s more, it continues to be researched both as part of a potential combination therapy for some cancers. Brequinar exhibits antiviral activity against a broad spectrum of viruses including flaviviruses (dengue virus, West Nile virus, yellow fever virus, and Powassan virus) and also a plus-strand RNA alphavirus (Western equine encephalitis virus) and a negative-strand RNA rhabdovirus (vesicular stomatitis virus).