title: Small molecule inhibitors of SHP2 tyrosine phosphatase discovered by virtual screening.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Yu
authors.forename: Lan
authors.initials: L
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Sijiu
authors.initials: S
authors.lastname: Liu
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D001557:Benzenesulfonates / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D016415:Sequence Alignment; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D018909:src Homology Domains
chemical_list: D001557:Benzenesulfonates; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D054852:Small Molecule Libraries; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11