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 , 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 , which possesses excellent potency and a promising PK profile in rodents.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9923835 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.2c00454 | DOI Listing |
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