Brequinar Explained

Brequinar (DuP-785) is a drug that acts as a potent and selective inhibitor of the enzyme dihydroorotate dehydrogenase. It blocks synthesis of pyrimidine based nucleotides in the body and so inhibits cell growth. Brequinar was invented by DuPont Pharmaceuticals in the 1980s.^[1] In 2001, Bristol-Myers Squibb acquired DuPont, and in 2017, Clear Creek Bio acquired the rights to brequinar from BMS.^[2]

Brequinar has been investigated as an immunosuppressant for preventing rejection after organ transplant and also as an anti-cancer drug, but was not accepted for medical use in either application largely due to its narrow therapeutic dose range and severe side effects when dosed inappropriately.^{[3] [4]} It has been researched both as part of a potential combination therapy for some cancers,^{[5] [6]} or alternatively as an antiparasitic,^[7] or antiviral drug.^{[8] [9] [10]} Clear Creek Bio is currently developing brequinar as a potential treatment for COVID-19.^[11]

Inhibition of dihydroorotate dehydrogenase activity by brequinar may represent an efficient approach to the elimination of undifferentiated cells for safe PSC‐derived differentiated cells based therapies.^[12]

See also

• Leflunomide - Clinically used DHODH inhibitor
• Methotrexate - the most widely used pyrimidine synthesis inhibitor

Notes and References

1. Dexter DL, Hesson DP, Ardecky RJ, Rao GV, Tippett DL, Dusak BA, Paull KD, Plowman J, DeLarco BM, Narayanan VL . 6 . Activity of a novel 4-quinolinecarboxylic acid, NSC 368390 [6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarb oxylic acid sodium salt], against experimental tumors ]. Cancer Research . 45 . 11 Pt 1 . 5563–5568 . November 1985 . 4053030 .
2. Web site: May 3, 2022 . Bristol Myers Squibb Company History Timeline .
3. Cramer DV . Brequinar sodium . Pediatric Nephrology . 9 Suppl . S52-5 . 1995 . 7492488 . 10.1007/bf00867685 . 28974570 .
4. Peters GJ . Re-evaluation of Brequinar sodium, a dihydroorotate dehydrogenase inhibitor . Nucleosides, Nucleotides & Nucleic Acids . 37 . 12 . 666–678 . 2018 . 30663496 . 10.1080/15257770.2018.1508692 . free .
5. Vyas VK, Ghate M . Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors . Mini Reviews in Medicinal Chemistry . 11 . 12 . 1039–55 . October 2011 . 21861807 . 10.2174/138955711797247707 .
6. Madak JT, Bankhead A, Cuthbertson CR, Showalter HD, Neamati N . Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer . Pharmacology & Therapeutics . 195 . 111–131 . March 2019 . 30347213 . 10.1016/j.pharmthera.2018.10.012 . 53036782 .
7. Boschi D, Pippione AC, Sainas S, Lolli ML . Dihydroorotate dehydrogenase inhibitors in anti-infective drug research . European Journal of Medicinal Chemistry . 183 . 111681 . December 2019 . 31557612 . 10.1016/j.ejmech.2019.111681 .
8. Li SF, Gong MJ, Sun YF, Shao JJ, Zhang YG, Chang HY . Antiviral activity of brequinar against foot-and-mouth disease virus infection in vitro and in vivo . Biomedicine & Pharmacotherapy . 116 . 108982 . August 2019 . 31146110 . 10.1016/j.biopha.2019.108982 . free .
9. Andersen PI, Krpina K, Ianevski A, Shtaida N, Jo E, Yang J, Koit S, Tenson T, Hukkanen V, Anthonsen MW, Bjoras M, Evander M, Windisch MP, Zusinaite E, Kainov DE . 6 . Novel Antiviral Activities of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine . Viruses . 11 . 10 . 964 . October 2019 . 31635418 . 6832696 . 10.3390/v11100964 . free .
10. Park JG, Ávila-Pérez G, Nogales A, Blanco-Lobo P, de la Torre JC, Martínez-Sobrido L . Identification and characterization of novel compounds with broad spectrum antiviral activity against influenza A and B viruses . Journal of Virology . 94. 7. January 2020 . 31941776 . 10.1128/JVI.02149-19 . 7081893 . free .
11. Web site: November 20, 2020 . Clear Creek Bio Doses First Patient in Phase 2 Outpatient Study of Brequinar to Treat COVID-19 .
12. Kondo, T . Selective eradication of pluripotent stem cells by inhibiting DHODH activity . Stem Cells . 39 . 1 . 33–42 . October 2021 . 33038285 . 10.1002/stem.3290 . 222280648 . 2115/82146 . free .