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6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2019 Feb 28; Vol. 62 (4), pp. 1793-1802. Date of Electronic Publication: 2019 Feb 16. - Publication Year :
- 2019
-
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.
- Subjects :
- Administration, Oral
Allosteric Regulation
Allosteric Site
Aminopyridines chemical synthesis
Aminopyridines pharmacokinetics
Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents pharmacokinetics
Cell Line, Tumor
Crystallography, X-Ray
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors pharmacokinetics
Female
Humans
Male
Mice, Inbred C57BL
Molecular Structure
Protein Tyrosine Phosphatase, Non-Receptor Type 11 chemistry
Pyrimidinones chemical synthesis
Pyrimidinones pharmacokinetics
Structure-Activity Relationship
Xenograft Model Antitumor Assays
Aminopyridines therapeutic use
Antineoplastic Agents therapeutic use
Enzyme Inhibitors therapeutic use
Neoplasms drug therapy
Protein Tyrosine Phosphatase, Non-Receptor Type 11 antagonists & inhibitors
Pyrimidinones therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 62
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30688459
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b01726