Design, synthesis and activity study of a novel PI3K degradation by hijacking VHL E3 ubiquitin ligase

Area of Science:

• Molecular Biology
• Biochemistry
• Oncology

Background:

• Phosphoinositide 3-kinase (PI3K) is crucial for cellular functions like growth, metabolism, proliferation, and apoptosis.
• Overexpression of PI3K is frequently observed in various cancers, making it a significant therapeutic target.
• Proteolytic Targeting Chimera (PROTAC) technology offers a novel approach to selectively degrade target proteins via the ubiquitin-proteasome system.

Purpose of the Study:

• To explore the development of VHL-based PROTACs targeting PI3K kinase, as previous PROTACs primarily utilized CRBN.
• To synthesize and screen a series of novel PROTAC molecules linking a PI3K inhibitor to a VHL ligand.
• To evaluate the feasibility of using VHL E3 ligase recruitment for PI3K degradation.

Main Methods:

• Design and synthesis of PROTAC molecules by conjugating a potent PI3K inhibitor with a VHL ligand via diverse linkers.
• Screening of the synthesized PROTAC library to identify compounds with high efficacy in degrading PI3K kinase.
• Biochemical assays to confirm PI3K degradation mediated by VHL-recruiting PROTACs.

Main Results:

• A series of novel VHL-based PROTACs targeting PI3K kinase were successfully synthesized.
• Screening identified a lead compound demonstrating significant PI3K degradation activity.
• The results confirm the efficacy of recruiting VHL E3 ligase for targeted PI3K degradation using PROTAC technology.

Conclusions:

• VHL-based PROTACs represent a viable strategy for the targeted degradation of PI3K kinase.
• This approach offers a promising new avenue for developing cancer therapeutics.
• Further investigation into VHL-recruiting PROTACs for PI3K inhibition is warranted.