Discovery of LC-SF-14, a selective dual inhibitor of SHP2 and FGFR for the treatment of FGFR2-driven gastric cancer.

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.