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

Src homology region 2-containing phosphatase 2 (SHP2) is overexpressed in various cancers and suppresses immune function while promoting tumor immune escape by regulating intracellular signaling pathways. Currently, the primary therapeutic strategies targeting SHP2 focus on inhibiting its catalytic activity or reducing its expression levels. However, SHP2 allosteric inhibitors face challenges in terms of efficacy, safety, and developmental difficulty when used as monotherapy. Consequently, several SHP2-PROTAC molecules have been developed. Given the limited substrate spectrum of ubiquitin-proteasome systems, we propose that autophagy-based degradation strategies possess greater advantages. Using SHP099 as the ligand of the protein of interest (POI), we designed and synthesized two series of SHP2-AUTACs. Among these, SA-8 demonstrated the optimal biological activity, showing significant antitumor activity and potent SHP2 degradation capability. Mechanistic studies revealed that SA-8 induced SHP2 degradation through ternary complex formation with both SHP2 and LC3, ultimately activating the autophagy-lysosome pathway. It was found that SA-8 can dose-dependently induce apoptosis in HeLa cells. This work not only validates the practical utility of the AUTAC strategy but also offers a promising therapeutic approach for developing next-generation target degraders. • SHP2-AUTACs were designed based on FBnG-HTL probe and LC3 ligand. • SA-8 induced SHP2 degradation by activating the autophagy lysosome pathway. • SA-8 exhibited excellent cytotoxicity, degradation activity, and SHP2 selectivity. • SA-8 can induce apoptosis in various cancer cells.