Discovery of a Novel Series of Imidazopyrazine Derivatives as Potent SHP2 Allosteric Inhibitors
Esther Torrente, Valentina Fodale, A Ciammaichella, Federica Ferrigno, Jesus M. Ontoria, Simona Ponzi, Ilaria Rossetti, Alessio Sferrazza, Jérôme Amaudrut, Antonino Missineo, Simone Esposito, Simone Palombo, Martina Nibbio, Mauro Cerretani, Monica Bisbocci, Antonella Cellucci, Annalise Di Marco, Cristina Alli, Vincenzo Pucci, Carlo Toniatti, Alessia Petrocchi
Abstract
Protein tyrosine phosphatase SHP2 is an oncogenic protein that can regulate different cytokine receptor and receptor tyrosine kinase signaling pathways. We report here the identification of a novel series of SHP2 allosteric inhibitors having an imidazopyrazine 6,5-fused heterocyclic system as the central scaffold that displays good potency in enzymatic and cellular assays. SAR studies led to the identification of compound 8, a highly potent SHP2 allosteric inhibitor. X-ray studies showed novel stabilizing interactions with respect to known SHP2 inhibitors. Subsequent optimization allowed us to identify analogue 10, which possesses excellent potency and a promising PK profile in rodents.