A high affinity pan-PI3K binding module supports selective targeted protein degradation of PI3Kα

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Class I phosphoinositide 3-kinases (PI3Ks) are crucial for cellular growth, insulin signaling, and glucose homeostasis.
• Broad PI3K inhibitors cause significant adverse effects, hindering drug development.
• The PI3Kα isoform is frequently mutated in cancer.

Purpose of the Study:

• To develop a selective degrader for the PI3Kα isoform.
• To overcome the toxicities associated with non-selective PI3K inhibitors.
• To create a research tool for studying PI3K biology.

Main Methods:

• Incorporation of a high-affinity binding module into a cereblon-targeted (CRBN) degrader.
• Systematic proteomics to optimize degrader selectivity and potency.
• Development of WJ112-14, a PI3Kα-specific nanomolar degrader.

Main Results:

• Demonstrated selective degradation of PI3Kα using a CRBN-based degrader.
• Optimized molecular features for enhanced degrader potency and selectivity.
• Successfully created WJ112-14, a potent PI3Kα-specific degrader.

Conclusions:

• Selective degradation of PI3Kα is achievable with targeted molecular designs.
• WJ112-14 serves as a valuable research tool for PI3Kα biology.
• This approach offers a promising strategy to target oncogenic PI3Kα while mitigating adverse effects.