Brequinar (DUP785) is a potent inhibitor of dihydroorotatedehydrogenase (DHODH) with an IC50 of 5.2 nM for human DHODH. Brequinar has potent activities against a broad spectrum of viruses.
Dihydroorotate dehydrogenase (DHODH) is the only redox enzyme of the six enzymes involved in the de novo biosynthesis pathway. It catalyses the oxidation of dihydroorotate (DHO) to orotate (ORO) and the electrons are transferred via the involvement of two cofactors (flavin mononucleotide (FMN) and either nicotinamide adenine dinucleotide (NAD) or ubiquinone (CoQ)) in the respiratory mitochondrial chain[5]. Brequinar is a potent inhibitor of the mitochondrial DHODH, a rate-limiting enzyme in the pyrimidine de novo nucleotide synthesis. In phase I clinical studies at the maximum tolerated dose (MTD) Brequinar induced a long-term inhibition of DHODH in white blood cells (WBC) and a long-term depletion of plasma uridine[6]. Moreover, combination of Brequinar with doxorubicin resulted in synergistic and additive cell growth inhibition in melanoma cells. In addition, in vivo studies with this combination of drugs demonstrated an almost 90% tumor regression in nude mice bearing melanoma tumors[7].
搜索
