Chemically Linked Vemurafenib Inhibitors Promote an Inactive BRAF^V600E Conformation.

ABSTRACT: The BRAF kinase, within the mitogen activated protein kinase (MAPK) signaling pathway, harbors activating mutations in about half of melanomas and to a significant extent in many other cancers. A single valine to glutamic acid substitution at residue 600 (BRAF^V600E) accounts for about 90% of these activating mutations. While BRAF^V600E-selective small molecule inhibitors, such as debrafenib and vemurafenib, have shown therapeutic benefit, almost all patients develop resistance. Resistance often arises through reactivation of the MAPK pathway, typically through mutation of upstream RAS, downstream MEK, or splicing variants. RAF kinases signal as homo- and heterodimers, and another complication associated with small molecule BRAF^V600E inhibition is drug-induce

SUBMITTER: Grasso M 

PROVIDER: S-EPMC5108658 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature