Discovery and Preclinical Characterization of I-0436650, a Selective SHP2 Allosteric Inhibitor for RAS-Driven Cancers
Alina Ciammaichella, Francesca Puca, Danilo Fabbrini, Pietro Randazzo, Ilaria Rossetti, Alessio Sferrazza, Federica Ferrigno, Alessandro Grillo, Esther Torrente, Costanza Iaccarino, Jérôme Amaudrut, Antonella Cellucci, Annalise Di Marco, Simone Palombo, Simone Esposito, Monica Bisbocci, Maria Vittoria Orsale, Martina Nibbio, Antonino Missineo, Francesco Scalabrì, Valentina Fodale, Vincenzo Pucci, Cristina Alli, Romano Di Fabio, Christian Montalbetti, Alessandro Carugo, Carlo Toniatti, Alessia PetrocchiAbstract
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.