Discovery of Selective Small Molecule Degraders of BRAF-V600E

BRAF
is among the most frequently mutated oncogenes in human cancers.
Multiple small molecule BRAF kinase inhibitors have been approved
for treating melanoma carrying BRAF-V600 mutations. However, the benefits
of BRAF kinase inhibitors are generally short-lived. Small molecule-mediated
targeted protein degradation has recently emerged as a novel pharmaceutical
strategy to remove disease proteins through hijacking the cellular
ubiquitin proteasome system (UPS). In this study, we developed thalidomide-based
heterobifunctional compounds that induced selective degradation of
BRAF-V600E, but not the wild-type BRAF. Downregulation of BRAF-V600E
suppressed the MEK/ERK kinase cascade in melanoma cells and impaired
cell growth in culture. Abolishing the interaction between degraders
and cereblon or blocking the UPS significantly impaired the activities
of these degraders, validating a mechanistic role of UPS in mediating
targeted degradation of BRAF-V600E. These findings highlight a new
approach to modulate the functions of oncogenic BRAF mutants and provide
a framework to treat BRAF-dependent human cancers.