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Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor.
Garcia Fortanet, Jorge; Chen, Christine Hiu-Tung; Chen, Ying-Nan P; Chen, Zhouliang; Deng, Zhan; Firestone, Brant; Fekkes, Peter; Fodor, Michelle; Fortin, Pascal D; Fridrich, Cary; Grunenfelder, Denise; Ho, Samuel; Kang, Zhao B; Karki, Rajesh; Kato, Mitsunori; Keen, Nick; LaBonte, Laura R; Larrow, Jay; Lenoir, Francois; Liu, Gang; Liu, Shumei; Lombardo, Franco; Majumdar, Dyuti; Meyer, Matthew J; Palermo, Mark; Perez, Lawrence; Pu, Minying; Ramsey, Timothy; Sellers, William R; Shultz, Michael D; Stams, Travis; Towler, Christopher; Wang, Ping; Williams, Sarah L; Zhang, Ji-Hu; LaMarche, Matthew J.
Afiliação
  • Garcia Fortanet J; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Chen CH; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Chen YN; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Chen Z; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Deng Z; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Firestone B; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Fekkes P; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Fodor M; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Fortin PD; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Fridrich C; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Grunenfelder D; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Ho S; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Kang ZB; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Karki R; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Kato M; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Keen N; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • LaBonte LR; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Larrow J; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Lenoir F; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Liu G; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Liu S; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Lombardo F; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Majumdar D; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Meyer MJ; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Palermo M; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Perez L; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Pu M; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Ramsey T; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Sellers WR; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Shultz MD; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Stams T; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Towler C; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Wang P; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Williams SL; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • Zhang JH; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
  • LaMarche MJ; Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, Uni
J Med Chem ; 59(17): 7773-82, 2016 09 08.
Article em En | MEDLINE | ID: mdl-27347692
ABSTRACT
SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piperidinas / Pirazinas / Pirimidinas / Proteína Tirosina Fosfatase não Receptora Tipo 11 / Antineoplásicos Idioma: En Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piperidinas / Pirazinas / Pirimidinas / Proteína Tirosina Fosfatase não Receptora Tipo 11 / Antineoplásicos Idioma: En Ano de publicação: 2016 Tipo de documento: Article