Small molecule inhibitors of SHP2 tyrosine phosphatase discovered by virtual screening

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Yu, Zhi-Hong¹  Chen, Lan^1,2  Wu, Li^1,2  Liu, Sijiu¹  Wang, Lina¹  Zhang, Zhong-Yin^1,2 

[1] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[2] Indiana Univ Sch Med, Chem Genom Core Facil, Indianapolis, IN 46202 USA

关键词: SHP2 inhibitor;    Protein tyrosine phosphatase (PTP);    Virtual screening;    Molecular dynamics simulation;    Drug discovery;   

DOI  :  10.1016/j.bmcl.2011.05.078

来源: Elsevier

【 摘 要 】

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. (C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

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