2. Academic Validation
  3. Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor

Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor

  • J Med Chem. 2016 Sep 8;59(17):7773-82. doi: 10.1021/acs.jmedchem.6b00680.
Jorge Garcia Fortanet 1,  Christine Hiu-Tung Chen 1,  Ying-Nan P Chen 1,  Zhouliang Chen 1,  Zhan Deng 1,  Brant Firestone 1,  Peter Fekkes 1,  Michelle Fodor 1,  Pascal D Fortin 1,  Cary Fridrich 1,  Denise Grunenfelder 1,  Samuel Ho 1,  Zhao B Kang 1,  Rajesh Karki 1,  Mitsunori Kato 1,  Nick Keen 1,  Laura R LaBonte 1,  Jay Larrow 1,  Francois Lenoir 1,  Gang Liu 1,  Shumei Liu 1,  Franco Lombardo 1,  Dyuti Majumdar 1,  Matthew J Meyer 1,  Mark Palermo 1,  Lawrence Perez 1,  Minying Pu 1,  Timothy Ramsey 1,  William R Sellers 1,  Michael D Shultz 1,  Travis Stams 1,  Christopher Towler 1,  Ping Wang 1,  Sarah L Williams 1,  Ji-Hu Zhang 1,  Matthew J LaMarche 1
Affiliations

Affiliation

  • 1 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, United States.
PMID: 27347692 DOI: 10.1021/acs.jmedchem.6b00680
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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