Discovery of SA-8 as a potent SHP2-AUTAC degrader in cancer therapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Src homology region 2-containing phosphatase 2 (SHP2) is overexpressed in cancers, promoting tumor growth and immune evasion.
• Current SHP2 inhibitors have limitations in efficacy, safety, and development.
• Autophagy-based degradation offers potential advantages over ubiquitin-proteasome systems for targeted protein removal.

Purpose of the Study:

• To design and synthesize novel SHP2-targeting autophagy-based chimeric molecules (AUTACs).
• To evaluate the efficacy of SHP2-AUTACs in degrading SHP2 and exhibiting antitumor activity.
• To elucidate the mechanism of action for SHP2 degradation via autophagy.

Main Methods:

• Design and synthesis of two series of SHP2-AUTACs using SHP099 as the ligand.
• Assessment of biological activity, including SHP2 degradation and antitumor effects.
• Mechanistic studies involving ternary complex formation and autophagy-lysosome pathway activation.

Main Results:

• SA-8, a lead SHP2-AUTAC, demonstrated potent SHP2 degradation and significant antitumor activity.
• SA-8 induced SHP2 degradation by forming a ternary complex with SHP2 and LC3, activating autophagy.
• SA-8 dose-dependently induced apoptosis in HeLa cancer cells.

Conclusions:

• The AUTAC strategy is a viable approach for targeted protein degradation.
• SA-8 represents a promising next-generation therapeutic candidate for SHP2-driven cancers.
• SHP2-AUTACs offer a novel therapeutic strategy for cancer treatment by hijacking the autophagy pathway.