{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Yu ZH"],"funding":["NCI NIH HHS"],"pagination":["4238-42"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC3128679"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["21(14)"],"pubmed_abstract":["SHP2, encoded by PTPN11, is a non-receptor protein tyrosine phosphatase (PTP) containing two tandem Src homology-2 (SH2) domains. It is expressed ubiquitously and plays critical roles in growth factor mediated processes, primarily by promoting the activation of the RAS/ERK signaling pathway. Genetic and biochemical studies have identified SHP2 as the first bona fide oncoprotein in the PTP superfamily, and a promising target for anti-cancer and anti-leukemia therapy. Here, we report a structure-based approach to identify SHP2 inhibitors with a novel scaffold. Through sequential virtual screenings and in vitro inhibition assays, a reversible competitive SHP2 inhibitor (C21) was identified. C21 is structurally distinct from all known SHP2 inhibitors. Combining molecular dynamics simulation and binding free energy calculation, a most likely binding mode of C21 with SHP2 is proposed, and further validated by site-directed mutagenesis and structure-activity relationship studies. This binding mode is consistent with the observed potency and specificity of C21, and reveals the molecular determinants for further optimization based on the new scaffold."],"journal":["Bioorganic & medicinal chemistry letters"],"pubmed_title":["Small molecule inhibitors of SHP2 tyrosine phosphatase discovered by virtual screening."],"pmcid":["PMC3128679"],"funding_grant_id":["R01 CA152194","R01 CA126937","R01 CA126937-05","R01 CA152194-02","CA126937","CA152194"],"pubmed_authors":["Wu L","Zhang ZY","Chen L","Yu ZH","Liu S","Wang L"],"additional_accession":[]},"is_claimable":false,"name":"Small molecule inhibitors of SHP2 tyrosine phosphatase discovered by virtual screening.","description":"SHP2, encoded by PTPN11, is a non-receptor protein tyrosine phosphatase (PTP) containing two tandem Src homology-2 (SH2) domains. It is expressed ubiquitously and plays critical roles in growth factor mediated processes, primarily by promoting the activation of the RAS/ERK signaling pathway. Genetic and biochemical studies have identified SHP2 as the first bona fide oncoprotein in the PTP superfamily, and a promising target for anti-cancer and anti-leukemia therapy. Here, we report a structure-based approach to identify SHP2 inhibitors with a novel scaffold. Through sequential virtual screenings and in vitro inhibition assays, a reversible competitive SHP2 inhibitor (C21) was identified. C21 is structurally distinct from all known SHP2 inhibitors. Combining molecular dynamics simulation and binding free energy calculation, a most likely binding mode of C21 with SHP2 is proposed, and further validated by site-directed mutagenesis and structure-activity relationship studies. This binding mode is consistent with the observed potency and specificity of C21, and reveals the molecular determinants for further optimization based on the new scaffold.","dates":{"release":"2011-01-01T00:00:00Z","publication":"2011 Jul","modification":"2021-02-20T04:28:29Z","creation":"2019-03-27T03:06:38Z"},"accession":"S-EPMC3128679","cross_references":{"pubmed":["21669525"],"doi":["10.1016/j.bmcl.2011.05.078"]}}