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Re-evaluation of Brequinar sodium, a dihydroorotate dehydrogenase inhibitor

DUP-785 (Brequinar sodium) is a potent inhibitor of the mitochondrial dihydroorotate dehydrogenase (DHO-DH), 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 DHO-DH in white blood cells (WBC) and a long-term depletion of plasma uridine. These two parameters were related to severe myelosuppression, so that in Phase II studies the dose of Brequinar was decreased considerably. We further characterized the mechanism of DHO-DH enzyme inhibition while in blood samples of patients entered into Phase II studies we evaluated DHO-DH inhibition in WBC and plasma uridine depletion. With Electron Spin Resonance it was demonstrated that DHO-DH produced oxygen radical formation, which was inhibited by Brequinar. In the Phase II study depending on the dose (600 to 2000 mg/m2), uridine decreased to 20% (at the highest dose) or to 80-85% (at the middle dose) or did not change, which was associated with inhibition of DHO-DH (1% activity left vs 11 and 24% left). Inhibition of DHO-DH in the tumor of the latter patient was moderate as well (12% activity left). Brequinar was inactive in all tumor types evaluated possibly because of high uridine levels in the tumor. In conclusion, Brequinar was inactive against solid tumors, but DHO-DH inhibition was associated with myeloid toxicity, which may explain its potential for treatment of leukemia or inflammatory diseases.

 

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Brequinar sodium (DUP-785) is a potent inhibitor of dihydroorotate dehydrogenase (DHO-DH), an enzyme that plays a key role in the synthesis of pyrimidine nucleotides. The drug was evaluated in Phase I and Phase II clinical studies, where it was found to induce long-term inhibition of DHO-DH in white blood cells (WBC) and depletion of plasma uridine, which were related to severe myelosuppression.

In Phase II studies, the dose of Brequinar was decreased considerably to minimize myelosuppression. At different doses (ranging from 600 to 2000 mg/m2), uridine levels decreased to varying degrees, which was associated with inhibition of DHO-DH activity. Electron Spin Resonance studies demonstrated that Brequinar inhibited oxygen radical formation by DHO-DH.

The drug was found to be inactive against solid tumors, possibly due to high uridine levels in the tumor. However, inhibition of DHO-DH was associated with myeloid toxicity, suggesting that Brequinar may have potential for the treatment of leukemia or inflammatory diseases. In conclusion, Brequinar sodium is a promising drug candidate that may have therapeutic applications in certain hematological and inflammatory conditions.

Related Products

Cat.No. Product Name Information
S6626 Brequinar Brequinar is an inhibitor of dihydroorotate dehydrogenase (DHODH) with an IC50 of ∼20 nM in vitro.

Related Targets

Dehydrogenase