Discovery and Preclinical Characterization of I-0436650, a Selective SHP2 Allosteric Inhibitor for RAS-Driven Cancers.

SHP2 (Src homology 2 (SH2)-containing protein tyrosine phosphatase 2) is a tyrosine phosphatase that plays a critical role in numerous physiological and pathological cellular processes, including cell proliferation, survival, and migration through the regulation of multiple signaling pathways, such as RAS-RAF-mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI3K)-AKT, Janus tyrosine kinase (JAK), and signal transducer and activator of transcription pathways (STAT) in response to cytokines and growth factors. Through extensive structure-based optimization, we identified I-0436650, a preclinical candidate with an excellent pharmacological profile. I-0436650 is a low nanomolar allosteric inhibitor of human wild-type (wt) SHP2 and strongly inhibits ERK phosphorylation in cells. It exhibits antiproliferative activity in EGFR- and RAS-dependent cell lines, suppresses tumor growth as a single agent in xenograft models, and delays tumor relapse when combined with inhibitors of the same pathway, demonstrating the potential of vertical inhibition strategies.