Development of a potent small-molecule degrader against oncogenic BRAF^V600E protein that evades paradoxical MAPK activation.

ABSTRACT: BRAF mutations are frequently observed in melanoma and hairy-cell leukemia. Currently approved rapidly accelerated fibrosarcoma (RAF) kinase inhibitors targeting oncogenic BRAF V600 mutations have shown remarkable efficacy in the clinic, but their therapeutic benefits are occasionally hampered by acquired resistance due to RAF dimerization-dependent reactivation of the downstream MAPK pathway, which is known as paradoxical activation. There is also a concern that paradoxical activation of the MAPK pathway may trigger secondary cancer progression. In this study, we developed chimeric compounds, proteolysis targeting chimeras (PROTACs), that target BRAF^V600E protein for degradation. CRBN(BRAF)-24, the most effective chimera, potently degraded BRAF^V600E in a ubiquitin-pr

SUBMITTER: Ohoka N 

PROVIDER: S-EPMC9357609 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature