Mutant-selective degradation by BRAF-targeting PROTACs.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Over 300 BRAF mutations exist, but current therapies target only V600 mutants.
• Acquired resistance to BRAF inhibitors often involves RAF lesions, necessitating novel therapeutic strategies.
• Existing treatments face limitations in targeting diverse BRAF mutants and overcoming resistance mechanisms.

Purpose of the Study:

• To develop and evaluate Proteolysis Targeting Chimeras (PROTACs) for targeting diverse BRAF mutants.
• To overcome limitations of current BRAF inhibitor-based therapies.
• To achieve selective degradation of mutant BRAF while sparing wild-type BRAF (BRAF^WT).

Main Methods:

• Utilized vemurafenib-based PROTACs to induce ubiquitination and degradation of BRAF mutants.
• Assessed degradation of all BRAF mutant classes and wild-type BRAF (BRAF^WT) in cellular models.
• Evaluated the efficacy of the lead PROTAC in inhibiting cancer cell growth and in vivo xenograft models.

Main Results:

• Achieved low nanomolar degradation of all classes of BRAF mutants using vemurafenib-based PROTACs.
• Demonstrated selectivity by sparing degradation of wild-type RAF family members.
• The lead PROTAC showed superior efficacy over vemurafenib in preclinical cancer models, including in vivo efficacy in a Class 2 BRAF xenograft model.

Conclusions:

• PROTAC technology offers a novel approach to target mutant BRAF-driven cancers effectively.
• Achieved high selectivity for mutant BRAF degradation, sparing BRAF^WT due to conformational differences.
• This degradation-based strategy expands the therapeutic window and provides a promising anti-tumor drug modality.