2. Academic Validation
  3. Small Molecule Inhibitor that Stabilizes the Autoinhibited Conformation of the Oncogenic Tyrosine Phosphatase SHP2

Small Molecule Inhibitor that Stabilizes the Autoinhibited Conformation of the Oncogenic Tyrosine Phosphatase SHP2

  • J Med Chem. 2019 Feb 14;62(3):1125-1137. doi: 10.1021/acs.jmedchem.8b00513.
Xiaoqin Wu 1,  Gang Xu 2,  Xiaobo Li 1 2,  Weiren Xu 2,  Qianjin Li 1,  Wei Liu 2,  Karen A Kirby 3,  Mignon L Loh 4,  Jun Li 5,  Stefan G Sarafianos 3,  Cheng-Kui Qu 1 2
Affiliations

Affiliations

  • 1 Department of Pediatrics, Division of Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta , Emory University School of Medicine , Atlanta , Georgia 30322 , United States.
  • 2 Department of Medicine, Division of Hematology and Oncology, Case Comprehensive Cancer Center , Case Western Reserve University , Cleveland , Ohio 44106 , United States.
  • 3 Department of Pediatrics, Laboratory of Biochemical Pharmacology , Emory University School of Medicine , Atlanta , Georgia 30322 , United States.
  • 4 Department of Pediatrics, Division of Pediatric Hematology-Oncology , University of California, San Francisco , San Francisco , California 94122 , United States.
  • 5 School of Pharmacy , Anhui Medical University , Hefei 230032 , China.
PMID: 30457860 DOI: 10.1021/acs.jmedchem.8b00513
Abstract

Genetic mutations in the Phosphatase PTPN11 (SHP2) are associated with childhood leukemias. These mutations cause hyperactivation of SHP2 due to the disruption of the autoinhibitory conformation. By targeting the activation-associated protein conformational change, we have identified an SHP2 Inhibitor ( E)-1-(1-(5-(3-(2,4-dichlorophenyl)acryloyl)-2-ethoxy-4-hydroxybenzyl)-1,2,5,6-tetrahydropyridin-3-yl)-1 H-benzo[ d]imidazol-2(3 H)-one (LY6, 1) using computer-aided drug design database screening combined with cell-based assays. This compound inhibited SHP2 with an IC50 value of 9.8 μM, 7-fold more selective for SHP2 than the highly related SHP1. Fluorescence titration, thermal shift, and microscale thermophoresis quantitative binding assays confirmed its direct binding to SHP2. This compound was further verified to effectively inhibit SHP2-mediated cell signaling and proliferation. Furthermore, mouse and patient leukemia cells with PTPN11 activating mutations were more sensitive to this inhibitor than wild-type cells. This small molecule SHP2 Inhibitor has a potential to serve as a lead compound for further optimization studies to develop novel anti-SHP2 therapeutic agents.

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