2. Academic Validation
  3. 6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors

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

  • J Med Chem. 2019 Feb 28;62(4):1793-1802. doi: 10.1021/acs.jmedchem.8b01726.
Patrick Sarver,  Michael Acker,  Jeffrey T Bagdanoff,  Zhouliang Chen,  Ying-Nan Chen,  Homan Chan,  Brant Firestone,  Michelle Fodor,  Jorge Fortanet,  Huaixiang Hao,  Murphy Hentemann,  Mitsunori Kato,  Robert Koenig,  Laura R LaBonte,  Gang Liu,  Shumei Liu,  Chen Liu,  Eric McNeill,  Morvarid Mohseni,  Martin Sendzik,  Travis Stams,  Stan Spence,  Victoriano Tamez,  Ritesh Tichkule,  Christopher Towler,  Hongyun Wang,  Ping Wang,  Sarah L Williams,  Bing Yu,  Matthew J LaMarche
PMID: 30688459 DOI: 10.1021/acs.jmedchem.8b01726
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.

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