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6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors

Sarver, Patrick and Acker, Michael and Bagdanoff, Jeffrey and Chen, Zhuoliang and Chen, Ying-Nan and Chan, Ho Man and Firestone, Brant and Fodor, Michelle and Garcia Fortanet, Jorge and Hao, Huaixiang and Hentemann, Martin and Kato, Mitsunori and Koenig, Robert and La Bonte, Laura and Liu, Gang and Liu, Shumei and Liu, Chen and McNeill, Eric and Mohseni, Mori and Sendzik, Martin and Stams, Travis and Spence, Stan and Tamez Jr., Victoriano and Tichkule, Ritesh and Towler, Christopher and Wang, Hongyun and Wang, Ping and Williams, Sarah and Yu, Bing (2019) 6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors. Journal of Medicinal Chemistry, 62 (4). pp. 1793-1802. ISSN 15204804

Abstract

Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway. In the preceding manuscript, we described the optimization of a fused, bicyclic screening hit for potency, selectivity, and physicochemical properties in order to further expand the chemical diversity of allosteric SHP2 inhibitors. In this manuscript, we describe the further expansion of our approach, morphing the fused, bicyclic system into a novel monocyclic pyrimidinone scaffold through our understanding of SAR and use of structure-based design. These studies led to the identification of SHP394 (1), an orally efficacious inhibitor of SHP2, with high lipophilic efficiency, improved potency, and enhanced pharmacokinetic properties. We also report other pyrimidinone analogues with favorable pharmacokinetic and potency profiles. Overall, this work improves upon our previously described allosteric inhibitors and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism.

Item Type: Article
Keywords: SHP2, PTPN11, phosphatase, allosteric, cancer, SHP394
Date Deposited: 26 Mar 2019 00:45
Last Modified: 26 Mar 2019 00:45
URI: https://oak.novartis.com/id/eprint/37657

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