biostudies-literatureUnknown14(2)Torrente ECollezione Nazionale di Composti Chimici e Centro di screeningProtein 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 <b>8</b>, 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 <b>10</b>, which possesses excellent potency and a promising PK profile in rodents.ACS medicinal chemistry letters156-162https://www.ebi.ac.uk/biostudies/studies/S-EPMC9923835biostudies-literatureDiscovery of a Novel Series of Imidazopyrazine Derivatives as Potent SHP2 Allosteric Inhibitors.PMC9923835Fodale VAmaudrut JPucci VAlli CCiammaichella AFerrigno FMissineo ABisbocci MEsposito SPonzi SRossetti Idi Marco AToniatti CPalombo STorrente ENibbio MCellucci ASferrazza AOntoria JMCerretani MPetrocchi AfalseDiscovery of a Novel Series of Imidazopyrazine Derivatives as Potent SHP2 Allosteric Inhibitors.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 <b>8</b>, 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 <b>10</b>, which possesses excellent potency and a promising PK profile in rodents.2023-01-01T00:00:00Z2023 Feb2026-05-28T21:47:54.285Z2025-04-05T14:48:14.204ZS-EPMC99238353679343810.1021/acsmedchemlett.2c00454