2. Academic Validation
  3. Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors

Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors

  • J Med Chem. 2019 Feb 28;62(4):1781-1792. doi: 10.1021/acs.jmedchem.8b01725.
Jeffrey T Bagdanoff,  Zhouliang Chen,  Michael Acker,  Ying-Nan Chen,  Homan Chan,  Michael Dore,  Brant Firestone,  Michelle Fodor,  Jorge Fortanet,  Murphy Hentemann,  Mitsunori Kato,  Robert Koenig,  Laura R LaBonte,  Shumei Liu,  Movarid Mohseni 1,  Rukundo Ntaganda,  Patrick Sarver,  Troy Smith,  Martin Sendzik,  Travis Stams,  Stan Spence,  Christopher Towler 1,  Hongyun Wang,  Ping Wang,  Sarah L Williams,  Matthew J LaMarche
Affiliations

Affiliation

  • 1 Chemical and Pharmaceutical Profiling , Novartis Pharmaceuticals , 250 Massachusetts Avenue , Cambridge , Massachusetts 02139 , United States.
PMID: 30688462 DOI: 10.1021/acs.jmedchem.8b01725
Abstract

SHP2 is a nonreceptor protein tyrosine Phosphatase within the mitogen-activated protein kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. SHP2 also participates in the programed cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of SHP2 has been widely investigated, including in our previous reports describing SHP099 (2), which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies, reported here in the first of two papers, led to the identification of multiple 5,6-fused bicyclic scaffolds that bind to the same allosteric tunnel as 2. We demonstrate the structural diversity permitted by the tunnel pharmacophore and culminated in the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that modulate MAPK signaling in vivo. These studies also served as the basis for further scaffold morphing and optimization, detailed in the following manuscript.

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