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Publication Abstract from PubMed

Microtubule-targeting agents (MTAs) are some of the clinically most successful anti-cancer drugs. Unfortunately, instances of multidrug resistances to MTA have been reported, which highlights the need for developing MTAs with different mechanistic properties. One less explored class of MTAs are [1,2,4]triazolo[1,5-a]pyrimidines (TPs). These cytotoxic compounds are microtubule-stabilizing agents that inexplicably bind to vinblastine binding site on tubulin, which is typically targeted by microtubule-destabilizing agents. Here we used cellular, biochemical, and structural biology approaches to address this apparent discrepancy. Our results establish TPs as vinca-site microtubule-stabilizing agents that promote longitudinal tubulin contacts in microtubules, in contrast to classical microtubule-stabilizing agents that primarily promote lateral contacts. Additionally we observe that TPs studied here are not affected by p-glycoprotein overexpression, and suggest that TPs are promising ligands against multidrug-resistant cancer cells.

Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin.,Saez-Calvo G, Sharma A, Balaguer FA, Barasoain I, Rodriguez-Salarichs J, Olieric N, Munoz-Hernandez H, Berbis MA, Wendeborn S, Penalva MA, Matesanz R, Canales A, Prota AE, Jimenez-Barbero J, Andreu JM, Lamberth C, Steinmetz MO, Diaz JF Cell Chem Biol. 2017 Jun 22;24(6):737-750.e6. doi:, 10.1016/j.chembiol.2017.05.016. Epub 2017 Jun 1. PMID:28579361^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.