Discovery of novel PROTACs based on multi-targeted angiogenesis inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Anti-angiogenesis is a validated cancer treatment strategy, but resistance to inhibitors limits efficacy.
• Proteolysis Targeting Chimeras (PROTACs) offer advantages over traditional drugs, including lower toxicity and reduced resistance.
• Developing novel therapeutic strategies is crucial to overcome drug resistance in cancer treatment.

Purpose of the Study:

• To design and synthesize novel Proteolysis Targeting Chimeras (PROTACs) based on a multi-targeted angiogenesis inhibitor.
• To evaluate the potential of these novel PROTACs in degrading target proteins in cancer cell lines.
• To investigate the mechanism of action for BRAF protein degradation mediated by PROTACs.

Main Methods:

• Synthesis of novel bifunctional PROTAC molecules.
• In vitro biological evaluation in various cancer cell lines.
• Analysis of protein degradation pathways, including target binding and E3 ubiquitin ligase dependency.

Main Results:

• The synthesized PROTACs demonstrated potential in degrading BRAF protein.
• PROTAC-1-mediated BRAF degradation was confirmed to be dependent on target protein binding and E3 ubiquitin ligase.
• Preliminary evaluations suggest these PROTACs could be effective against drug-resistant tumors.

Conclusions:

• Novel PROTACs based on S5 exhibit promising BRAF protein degradation capabilities.
• The mechanism of action involves the ubiquitin-proteasome system and E3 ligase recruitment.
• These findings support the potential of PROTACs in overcoming clinical resistance associated with traditional angiogenesis inhibitors.