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Discovery of Selective Small Molecule Degraders of BRAF-V600E

Author:
Han, Xiao-Ran  Chen, Liqun  Wei, Yuanqi  Yu, Weihua  Chen, Yanke  Zhang, Chunyan  Jiao, Bingyang  Shi, Tingting  Sun, Lei  Zhang, Chao  Xu, Yang  Lee, Matthew R.  Luo, Ying  Plewe, Michael B.  Wang, Jialiang  


Journal:
JOURNAL OF MEDICINAL CHEMISTRY


Issue Date:
2020


Abstract(summary):

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.


Page:
4069---4080


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