Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors
- 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.
- 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)
- Grant/Contract Number:
- AC02-06CH11357
- OSTI ID:
- 1503706
- Journal Information:
- Journal of Medicinal Chemistry, Vol. 62, Issue 4; ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)Copyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Web of Science
Design, Synthesis, and In Vitro Activity of Pyrazine Compounds
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journal | December 2019 |
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