Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors
| Autor: | Movarid Mohseni, Michelle Fodor, Jorge Garcia Fortanet, Shumei Liu, Laura R. LaBonte, Rukundo Ntaganda, Jeffrey T. Bagdanoff, Sarah Williams, Robert Koenig, Travis Stams, Ho Man Chan, Michael Dore, Christopher Towler, Matthew J. LaMarche, Brant Firestone, Ping Wang, Troy Smith, Michael G. Acker, Murphy Hentemann, Ying-Nan Chen, Patrick James Sarver, Hongyun Wang, Stan Spence, Martin Sendzik, Mitsunori Kato, Zhouliang Chen |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
MAPK/ERK pathway
Male MAP Kinase Signaling System Allosteric regulation Protein Tyrosine Phosphatase Non-Receptor Type 11 Plasma protein binding Protein tyrosine phosphatase Pyrimidinones 01 natural sciences Heterocyclic Compounds 2-Ring Rats Sprague-Dawley 03 medical and health sciences Structure-Activity Relationship Allosteric Regulation Cell Line Tumor Drug Discovery Structure–activity relationship Animals Humans Enzyme Inhibitors Protein kinase A 030304 developmental biology 0303 health sciences Molecular Structure Chemistry Cell growth 0104 chemical sciences Cell biology Mice Inbred C57BL Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Microsomes Liver Molecular Medicine Pyrazoles Pharmacophore Allosteric Site Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 62(4) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|