6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors
Open accessAbstract
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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The reporting of SHP099 is a milestone for small molecule SHP2 allosteric inhibitors, which further led to the development of TNO-155.
“The reporting of SHP099 is a milestone for small molecule SHP2 allosteric inhibitors, which further led to the development of aforementioned SHP2 inhibitor in clinical trials, TNO-155.286,287”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [286]
This mechanism of action inhibits SHP2 activity through a metastable mechanism, leading to the inhibition of RAS/ERK signaling and suppressing RTK-driven proliferation of human cancer cells in vitro.
“This mechanism of action inhibits SHP2 activity through a metastable mechanism, leading to the inhibition of RAS/ERK signaling and suppressing RTK-driven proliferation of human cancer cells in vitro.286–288”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [286]
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- Authors
- Sarver, P., Acker, M., Bagdanoff, J. T., Chen, Z., Chen, Y.-N., Chan, H., Firestone, B., Fodor, M., Fortanet, J., Hao, H., Hentemann, M., Kato, M., Koenig, R., LaBonte, L. R., Liu, G., Liu, S., Liu, C., McNeill, E., Mohseni, M., Sendzik, M., Stams, T., Spence, S., Tamez, V., Tichkule, R., Towler, C., Wang, H., Wang, P., Williams, S. L., Yu, B., & LaMarche, M. J.
- Affiliations
- Novartis Pharmaceuticals , , , , 250 Massachusetts Avenue , , ,
- Novartis (United States) (US)
- Corresponding author
- LaMarche, Matthew J.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-01-28
- Volume
- 62
- Issue
- 4
- Pages
- 1793-1802
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2913920462
- Cited by
- 87
- References
- 39
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 12 · 2023: 9 · 2022: 12 · 2021: 20 · 2020: 16 · 2019: 4
- FWCI
- 4.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Medicinal Chemistry (publishedVersion, other-oa)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- SHP2, allosteric inhibitors, pyrimidinone, structure-activity relationship, structure-based design, oral bioavailability, pharmacokinetics, PD-1/PD-L1 pathway, cancer therapy, immunomodulation
- MeSH terms
- Administration, Oral, Allosteric Regulation, Allosteric Site, Aminopyridines, Animals, Antineoplastic Agents, Enzyme Inhibitors, Female, Humans, Male, Mice, Inbred C57BL, Neoplasms, Pyrimidinones, Structure-Activity Relationship, Molecular Structure, Crystallography, X-Ray, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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