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

Sarver, Patrick; Acker, Michael; Bagdanoff, Jeffrey T.; Chen, Zhouliang; Chen, Ying-Nan; Chan, Homan; Firestone, Brant; Fodor, Michelle; Fortanet, Jorge; Hao, Huaixiang; Hentemann, Murphy; Kato, Mitsunori; Koenig, Robert; LaBonte, Laura R.; Liu, Gang; Liu, Shumei; Liu, Chen; McNeill, Eric; Mohseni, Morvarid; Sendzik, Martin; Stams, Travis; Spence, Stan; Tamez, Victoriano; Tichkule, Ritesh; Towler, Christopher; Wang, Hongyun; Wang, Ping; Williams, Sarah L.; Yu, Bing; LaMarche, Matthew J.

doi:10.1021/acs.jmedchem.8b01726

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

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

DOI:https://doi.org/10.1021/acs.jmedchem.8b01726· OSTI ID:1503705

Sarver, Patrick ^[1]; Acker, Michael ^[1]; Bagdanoff, Jeffrey T. ^[1]; Chen, Zhouliang ^[1]; Chen, Ying-Nan ^[1]; Chan, Homan ^[1]; Firestone, Brant ^[1]; Fodor, Michelle ^[1]; Fortanet, Jorge ^[1]; Hao, Huaixiang ^[1]; Hentemann, Murphy ^[1]; Kato, Mitsunori ^[1]; Koenig, Robert ^[1]; LaBonte, Laura R. ^[1]; Liu, Gang ^[1]; Liu, Shumei ^[1]; Liu, Chen ^[1]; McNeill, Eric ^[1]; Mohseni, Morvarid ^[1]; Sendzik, Martin ^[1] more »

Novartis Pharmaceuticals, Cambridge, MA (United States)

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.

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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:: 1503705

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

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Cited by: 53 works

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Design, synthesis, biological evaluation, common feature pharmacophore model and molecular dynamics simulation studies of ethyl 4-(phenoxymethyl)-2-phenylthiazole-5-carboxylate as Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors Wu, Jingwei; Li, Weiya; Zheng, Zhihui Journal of Biomolecular Structure and Dynamics https://doi.org/10.1080/07391102.2020.1726817	journal	February 2020
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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Peptides and proteins
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Rodent models
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Title: 6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors

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