Journal Article

Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAFsup.V600E Protein

Pandini, Marta, Gianquinto, Eleonora, Maione, Federica, Be, Oddo, Daniele, Spyrakis, Francesca, Gionfriddo, Giulia, Marini, Elisabetta, Di Nicolantonio, Federica, Rolando, Barbara, Kovachka, Sandra, Gastaldi, Simone, Blua, Federica, Giorgis, Marta, Marchiò, Serena, Marino, Marco

2022

Overview

BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAF[sup.V600E] mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of BRAF[sup.V600E] has been proposed as an alternative strategy to avoid the onset of resistance. In this study, we designed a series of compounds where the BRAF kinase inhibitor encorafenib was conjugated to pomalidomide through different linkers. The synthesized compounds maintained their ability to inhibit the kinase activity of mutated BRAF with IC[sub.50] values in the 40–88 nM range. Selected compounds inhibited BRAF[sup.V600E] signaling and cellular proliferation of A375 and Colo205 tumor cell lines. Compounds 10 and 11, the most active of the series, were not able to induce degradation of mutated BRAF. Docking and molecular dynamic studies, conducted in comparison with the efficient BRAF degrader P5B, suggest that a different orientation of the linker bearing the pomalidomide substructure, together with a decreased mobility of the solvent-exposed part of the conjugates, could explain this behavior.

• Publisher: MDPI AG
• Subject: Antimitotic agents / Antineoplastic agents / Melanoma / Molecular dynamics