The Dihydroorotate Dehydrogenase Inhibitor Brequinar Is Synergistic with ENT1/2 Inhibitors.

Autor:	Cuthbertson CR; Department of Medicinal Chemistry, College of Pharmacy and the Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States., Guo H; Department of Medicinal Chemistry, College of Pharmacy and the Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States., Kyani A; Department of Medicinal Chemistry, College of Pharmacy and the Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States., Madak JT; Department of Medicinal Chemistry, College of Pharmacy and the Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States., Arabzada Z; Department of Medicinal Chemistry, College of Pharmacy and the Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States., Neamati N; Department of Medicinal Chemistry, College of Pharmacy and the Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.
Jazyk:	angličtina
Zdroj:	ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2020 Nov 23; Vol. 3 (6), pp. 1242-1252. Date of Electronic Publication: 2020 Nov 23 (Print Publication: 2020).
DOI:	10.1021/acsptsci.0c00124
Abstrakt:	The dihydroorotate dehydrogenase (DHODH) inhibitor brequinar failed all clinical trials for solid tumors. To investigate mechanisms to increase brequinar's efficacy, we employed a combination strategy to simultaneously inhibit the nucleotide salvage pathways. Brequinar is synergistic with the equilibrative nucleoside transporter (ENT) inhibitor dipyridamole, but not the concentrative nucleoside transporter inhibitor phlorizin. This synergy carries over to ENT1/2 inhibition, but not ENT4. Our previously described brequinar analogue 41 was also synergistic with dipyridamole as were the FDA-approved DHODH inhibitors leflunomide and teriflunomide but the latter required much higher concentrations than brequinar. Therefore, a combination of brequinar and ENT inhibitors presents a potential anti-cancer strategy in select tumors. Competing Interests: The authors declare no competing financial interest. (© 2020 American Chemical Society.)
Databáze:	MEDLINE
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