| Literature DB >> 32778845 |
Ganna Posternak1,2,3, Xiaojing Tang1, Pierre Maisonneuve1, Ting Jin4, Hugo Lavoie4, Salima Daou1, Stephen Orlicky1, Theo Goullet de Rugy1, Lauren Caldwell1, Kin Chan1, Ahmed Aman2,5, Michael Prakesch2, Gennady Poda2,5, Pavel Mader1, Cassandra Wong1, Stefan Maier1, Julia Kitaygorodsky1,6, Brett Larsen1, Karen Colwill1, Zhe Yin1,7, Derek F Ceccarelli1, Robert A Batey3, Mikko Taipale6,8, Igor Kurinov9, David Uehling2, Jeff Wrana1,6, Daniel Durocher1,6, Anne-Claude Gingras1,6, Rima Al-Awar2, Marc Therrien10,11, Frank Sicheri12,13,14.
Abstract
The RAF family kinases function in the RAS-ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation and survival, enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAF(V600E) have shown great efficacy in the clinic, but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated. Here, we investigated a proteolysis-targeting chimera (PROTAC) approach to BRAF inhibition. The most effective PROTAC, termed P4B, displayed superior specificity and inhibitory properties relative to non-PROTAC controls in BRAF(V600E) cell lines. In addition, P4B displayed utility in cell lines harboring alternative BRAF mutations that impart resistance to conventional BRAF inhibitors. This work provides a proof of concept for a substitute to conventional chemical inhibition to therapeutically constrain oncogenic BRAF.Entities:
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Year: 2020 PMID： 32778845 PMCID： PMC7862923 DOI： 10.1038/s41589-020-0609-7
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040