SHP2 Allosteric Inhibitors(Viva Biotech)

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.

Src homology-2 domain-containing phosphatase 2 (SHP2) and fibroblast growth factor receptor 2 (FGFR2) are oncoproteins. Despite the tremendous progress achieved with SHP2 allosteric inhibitors, the efficacy of single-agent SHP2 inhibitor treatments has been shown to be suboptimal, based on recent clinical trial results. A previous study demonstrated the synergistic effect of the allosteric SHP2 inhibitor SHP099 and the FGFR inhibitor BGJ398, suggesting a potential combined targeted therapeutic option for cancer. In this study, we discovered a potent SHP2 and FGFR2 dual inhibitor, LC-SF-14, using a linked pharmacophore strategy and structural optimization. The active compound LC-SF-14 exhibited high inhibitory potency against both targets (71.6 nM and 8.9 nM, respectively) with a high degree of selectivity, as verified by kinase kinome and protein tyrosine phosphatase (PTP) enzyme profiling. LC-SF-14 effectively prevented the phosphorylation of FGFR2 and downstream signaling, resulting in tumor regression in vivo. These results indicate that the bifunctional molecule LC-SF-14, the first PTP- and receptor tyrosine kinase (RTK)-targeted dual inhibitor, is a promising lead for the treatment of cancers bearing SHP2 and FGFR oncogenic drivers.