BRAF is among the most frequently mutated oncogenes in human cancers, primarily due to mutations at codon 600. Three small molecule BRAF kinase inhibitors have been approved for treating melanoma patients carrying V600E/K mutations. Small molecule-mediated targeted protein degradation has recently emerged as novel technology for removal of disease causing proteins by hijacking the endogenous ubiquitin-proteasome system. In this study, we developed VHL-1 and thalidomide-based heterobifunctional compounds that selectively induced degradation of BRAF-V600E, but not the wild type BRAF. Reduced BRAF-V600E levels compromised the MEK/ERK kinase cascade and impaired melanoma cell growth in culture. Abolishing the interaction between degraders and cereblon or inhibition of proteasome greatly impaired the activities of these degraders. These findings demonstrated a novel strategy to modulate the functions of oncogenic BRAF and provide a framework to target non-catalytic functions of BRAF mutants.

Small molecule-mediated degradation of BRAF-V600E for the treatment of melanoma

2019 Fall National Meeting

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