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Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors

Bagdanoff, Jeffrey and Acker, Michael and Chan, Ho Man and Dore, Michael and Firestone, Brant and Fodor, Michelle and Garcia Fortanet, Jorge and Hentemann, Martin and Kato, Mitsunori and Koenig, Robert and La Bonte, Laura and Liu, Shumei and Chen, Zhuoliang and Chen, Ying-Nan and Mohseni, Mori and Ntaganda, Rukundo and Sarver, Patrick and Smith, Troy and Sendzik, Martin and Stams, Travis and Spence, Stan and Towler, Christopher and Wang, Hongyun and Wang, Ping and Williams, Sarah (2019) Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors. Journal of Medicinal Chemistry, 62 (4). pp. 1781-1792. ISSN 15204804

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.

Item Type: Article
Date Deposited: 26 Mar 2019 00:45
Last Modified: 26 Mar 2019 00:45
URI: https://oak.novartis.com/id/eprint/37653

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