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

• Published in: Journal of medicinal chemistry Vol. 62; no. 4; pp. 1793 - 1802
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.02.2019; Amer Chemical Soc; American Chemical Society (ACS)
• Subjects: Administration, Oral; Allosteric Regulation; Allosteric Site; Amines; Aminopyridines - chemical synthesis; Aminopyridines - pharmacokinetics; Aminopyridines - therapeutic use; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Chemistry, Medicinal; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - therapeutic use; Female; Humans; Inhibitors; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Life Sciences & Biomedicine; Male; Mice, Inbred C57BL; Molecular Structure; Neoplasms - drug therapy; Peptides and proteins; Pharmacology & Pharmacy; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - chemistry; Pyrimidinones - chemical synthesis; Pyrimidinones - pharmacokinetics; Pyrimidinones - therapeutic use; Rodent models; Science & Technology; Selectivity; Structure-Activity Relationship; Xenograft Model Antitumor Assays; ALLOSTERIC-INHIBITION; PTPN11; TYROSINE-PHOSPHATASE SHP2; MUTATIONS; IDENTIFICATION; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01726

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.