Off-target inhibition by active site-targeting SHP2 inhibitors

Abstract

Due to the involvement of SHP2 (SH2 domain-containing protein tyrosine phosphatase) in human disease, including Noonan syndrome and cancer, several inhibitors targeting SHP2 have been developed. Here, we report that the commonly used SHP2 inhibitor NSC-78788 does not exhibit robust inhibitory effects on growth factor-dependent MAPK (mitogen-activated protein kinase) pathway activation, and that the recently developed active site-targeting SHP2 inhibitors IIB-08, 11a-1, and GS-493 show off-target effects on ligand-evoked activation/trans-phosphorylation of the PDGFR{beta} (platelet-derived growth factor receptor {beta}). GS-493 also inhibits purified human PDGFR{beta} and SRC in vitro, whereas PDGFR{beta} inhibition by IIB-08 and 11a-1 occurs only in the cellular context. Our results argue for extreme caution in inferring specific functions for SHP2 based on studies using these inhibitors.