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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Discovery of Selective Small Molecule Degraders of BRAF-V600E
Xiao-Ran Han1,2, Liqun Chen2, Yuanqi Wei2
1Cullgen Inc., 12671 High Bluff Drive, Suite 130, San Diego, California 92130, United States.
Abstract:
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.
Insights
Researchers developed novel compounds to selectively degrade the BRAF-V600E oncoprotein in cancer cells. This targeted protein degradation approach offers a new strategy for treating BRAF-dependent cancers by disrupting key cellular pathways.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- BRAF mutations are common in human cancers, particularly melanoma.
- Current BRAF inhibitors provide limited long-term benefits due to resistance.
- Targeted protein degradation using the ubiquitin proteasome system (UPS) is a promising therapeutic strategy.
Purpose of the Study:
- To develop novel heterobifunctional compounds for targeted degradation of BRAF-V600E.
- To investigate the efficacy and mechanism of these degraders in melanoma cells.
- To explore a new therapeutic framework for BRAF-mutant cancers.
Main Methods:
- Design and synthesis of thalidomide-based heterobifunctional compounds.
- Assessment of BRAF-V600E degradation and MEK/ERK pathway inhibition in melanoma cell lines.
- Validation of UPS-dependent degradation by disrupting cereblon interaction or UPS function.
Main Results:
- Developed compounds selectively degraded BRAF-V600E, sparing wild-type BRAF.
- BRAF-V600E downregulation suppressed the MEK/ERK cascade and inhibited melanoma cell growth.
- Degrader activity was dependent on cereblon and functional UPS, confirming the mechanism.
Conclusions:
- Thalidomide-based degraders provide a novel approach to selectively eliminate oncogenic BRAF-V600E.
- Targeted protein degradation offers a potential strategy to overcome limitations of current BRAF inhibitors.
- This study establishes a framework for developing UPS-mediated therapies against BRAF-dependent cancers.
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