Structure and RAF family kinase isoform selectivity of type II RAF inhibitors tovorafenib and naporafenib.

ABSTRACT: Upon activation by RAS, RAF family kinases initiate signaling through the MAP kinase cascade to control cell growth, proliferation, and differentiation. Among RAF isoforms (ARAF, BRAF, and CRAF), oncogenic mutations are by far most frequent in BRAF. The BRAF^V600E mutation drives more than half of all malignant melanoma and is also found in many other cancers. Selective inhibitors of BRAF^V600E (vemurafenib, dabrafenib, encorafenib) are used clinically for these indications, but they are not effective inhibitors in the context of oncogenic RAS, which drives dimerization and activation of RAF, nor for malignancies driven by aberrantly dimerized truncation/fusion variants of BRAF. By contrast, a number of "type II" RAF inhibitors have been developed as potent inhibitors o

SUBMITTER: Tkacik E 

PROVIDER: S-EPMC10149214 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature