Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases

Ying-Nan P. Chen, Matthew J. LaMarche, Ho Man Chan, Peter Fekkes, Jorge Garcia-Fortanet, Michael G. Acker, Brandon Antonakos, Christine Hiu-Tung Chen, Zhouliang Chen, Vesselina G. Cooke, Jason R. Dobson, Zhan Deng, Feng Fei, Brant Firestone, Michelle Fodor, Cary Fridrich, Hui Gao, Denise Grunenfelder, Huai-Xiang Hao, Jaison Jacob, Samuel Ho, Kathy Hsiao, Zhao B. Kang, Rajesh Karki, Mitsunori Kato, Jay Larrow, Laura R. La Bonte, Francois Lenoir, Gang Liu, Shumei Liu, Dyuti Majumdar, Matthew J. Meyer, Mark Palermo, Lawrence Perez, Minying Pu, Edmund Price, Christopher Quinn, Subarna Shakya, Michael D. Shultz, Joanna Slisz, Kavitha Venkatesan, Ping Wang, Markus Warmuth, Sarah Williams, Guizhi Yang, Jing Yuan, Ji-Hu Zhang, Ping Zhu, Timothy Ramsey, Nicholas J. Keen, William R. Sellers (), Travis Stams () and Pascal D. Fortin ()
Additional contact information
Ying-Nan P. Chen: Novartis Institutes for Biomedical Research
Matthew J. LaMarche: Novartis Institutes for Biomedical Research
Ho Man Chan: Novartis Institutes for Biomedical Research
Peter Fekkes: Novartis Institutes for Biomedical Research
Jorge Garcia-Fortanet: Novartis Institutes for Biomedical Research
Michael G. Acker: Novartis Institutes for Biomedical Research
Brandon Antonakos: Novartis Institutes for Biomedical Research
Christine Hiu-Tung Chen: Novartis Institutes for Biomedical Research
Zhouliang Chen: Novartis Institutes for Biomedical Research
Vesselina G. Cooke: Novartis Institutes for Biomedical Research
Jason R. Dobson: Novartis Institutes for Biomedical Research
Zhan Deng: Novartis Institutes for Biomedical Research
Feng Fei: Novartis Institutes for Biomedical Research
Brant Firestone: Novartis Institutes for Biomedical Research
Michelle Fodor: Novartis Institutes for Biomedical Research
Cary Fridrich: Novartis Institutes for Biomedical Research
Hui Gao: Novartis Institutes for Biomedical Research
Denise Grunenfelder: Novartis Institutes for Biomedical Research
Huai-Xiang Hao: Novartis Institutes for Biomedical Research
Jaison Jacob: Novartis Institutes for Biomedical Research
Samuel Ho: Novartis Institutes for Biomedical Research
Kathy Hsiao: Novartis Institutes for Biomedical Research
Zhao B. Kang: Novartis Institutes for Biomedical Research
Rajesh Karki: Novartis Institutes for Biomedical Research
Mitsunori Kato: Novartis Institutes for Biomedical Research
Jay Larrow: Novartis Institutes for Biomedical Research
Laura R. La Bonte: Novartis Institutes for Biomedical Research
Francois Lenoir: Novartis Institutes for Biomedical Research
Gang Liu: Novartis Institutes for Biomedical Research
Shumei Liu: Novartis Institutes for Biomedical Research
Dyuti Majumdar: Novartis Institutes for Biomedical Research
Matthew J. Meyer: Novartis Institutes for Biomedical Research
Mark Palermo: Novartis Institutes for Biomedical Research
Lawrence Perez: Novartis Institutes for Biomedical Research
Minying Pu: Novartis Institutes for Biomedical Research
Edmund Price: Novartis Institutes for Biomedical Research
Christopher Quinn: Novartis Institutes for Biomedical Research
Subarna Shakya: Novartis Institutes for Biomedical Research
Michael D. Shultz: Novartis Institutes for Biomedical Research
Joanna Slisz: Novartis Institutes for Biomedical Research
Kavitha Venkatesan: Novartis Institutes for Biomedical Research
Ping Wang: Novartis Institutes for Biomedical Research
Markus Warmuth: Novartis Institutes for Biomedical Research
Sarah Williams: Novartis Institutes for Biomedical Research
Guizhi Yang: Novartis Institutes for Biomedical Research
Jing Yuan: Novartis Institutes for Biomedical Research
Ji-Hu Zhang: Novartis Institutes for Biomedical Research
Ping Zhu: Novartis Institutes for Biomedical Research
Timothy Ramsey: Novartis Institutes for Biomedical Research
Nicholas J. Keen: Novartis Institutes for Biomedical Research
William R. Sellers: Novartis Institutes for Biomedical Research
Travis Stams: Novartis Institutes for Biomedical Research
Pascal D. Fortin: Novartis Institutes for Biomedical Research

Nature, 2016, vol. 535, issue 7610, 148-152

Abstract: SHP099, a selective inhibitor of signalling meditator SHP2 with drug-like properties, has an allosteric mechanism of action whereby it stabilizes SHP2 in an auto-inhibited conformation, and suppresses RAS–ERK signalling and proliferation in receptor-tyrosine-kinase-driven cancer cell lines and mouse tumour xenograft models.

Date: 2016
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DOI: 10.1038/nature18621

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