Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors

Bagdanoff, Jeffrey T.; Chen, Zhouliang; Acker, Michael; Chen, Ying-Nan; Chan, Homan; Dore, Michael; Firestone, Brant; Fodor, Michelle; Fortanet, Jorge; Hentemann, Murphy; Kato, Mitsunori; Koenig, Robert; LaBonte, Laura R.; Liu, Shumei; Mohseni, Movarid; Ntaganda, Rukundo; Sarver, Patrick; Smith, Troy; Sendzik, Martin; Stams, Travis; Spence, Stan; Towler, Christopher; Wang, Hongyun; Wang, Ping; Williams, Sarah L.; LaMarche, Matthew J.

doi:10.1021/acs.jmedchem.8b01725

Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors

Journal Article · Mon Jan 28 04:00:00 EST 2019 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b01725· OSTI ID:1503706

Bagdanoff, Jeffrey T. ^[1]; Chen, Zhouliang ^[1]; Acker, Michael ^[1]; Chen, Ying-Nan ^[1]; Chan, Homan ^[1]; Dore, Michael ^[1]; Firestone, Brant ^[1]; Fodor, Michelle ^[1]; Fortanet, Jorge ^[1]; Hentemann, Murphy ^[1]; Kato, Mitsunori ^[1]; Koenig, Robert ^[1]; LaBonte, Laura R. ^[1]; Liu, Shumei ^[1]; Mohseni, Movarid ^[2]; Ntaganda, Rukundo ^[1]; Sarver, Patrick ^[1]; Smith, Troy ^[1]; Sendzik, Martin ^[1]; Stams, Travis ^[1] more »

Novartis Inst. for Biomedical Research, Cambridge, MA (United States)
Novartis Pharmaceuticals, Cambridge, MA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Industrial Macromolecular Crystallography Association; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1503706

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 4 Vol. 62; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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