Allosteric inhibition of SHP2: identification of a potent, selective, and orally efficacious phosphatase inhibitor
Open accessAbstract
SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.
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SHP099 binds simultaneously to the interfaces of the N-SH2, C-SH2 and PTP structural domains of SHP2, creating hydrogen bonding interactions with key amino acid residues (Arg111, Phe113 and Glu250) and stabilizing SHP2 in a closed, self-inhibited conformation.
“It binds simultaneously to the interfaces of the N-SH2, C-SH2 and PTP structural domains of SHP2, creating hydrogen bonding interactions with key amino acid residues (Arg111, Phe113 and Glu250) and stabilizing SHP2 in a closed, self-inhibited conformation.288”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [288]
SHP099 has favorable physicochemical properties, showing selectivity against 21 phosphatases and 66 kinases.
“SHP099 has favorable physicochemical properties, showing selectivity against 21 phosphatases and 66 kinases.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [288]
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 [288]
SHP2 inhibitors stabilize the auto-inhibited conformation of SHP2 and disrupt SOS1-mediated nucleotide exchange of KRAS.
“SHP2 inhibitors stabilize the auto-inhibited conformation of the enzyme and thereby disrupt SOS1-mediated nucleotide exchange of KRAS (11, 35, 36).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [35]
SHP2 inhibitors stabilize an inhibited enzyme conformation and disrupt the nucleotide exchange of KRAS mediated by SOS1.
“SHP2 inhibitors stabilize an inhibited enzyme conformation and, thus, disrupt the nucleotide exchange of KRAS mediated by SOS1 [56,59,60].”
From KRAS, a New Target for Precision Medicine in Colorectal Cancer? (2024) · cites this paper as [60]
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- Authors
- Garcia Fortanet, J., Chen, C. H.-T., Chen, Y.-N. P., Chen, Z., Deng, Z., Firestone, B., Fekkes, P., Fodor, M., Fortin, P. D., Fridrich, C., Grunenfelder, D., Ho, S., Kang, Z. B., Karki, R., Kato, M., Keen, N., LaBonte, L. R., Larrow, J., Lenoir, F., Liu, G., Liu, S., Lombardo, F., Majumdar, D., Meyer, M. J., Palermo, M., Perez, L., Pu, M., Ramsey, T., Sellers, W. R., Shultz, M. D., Stams, T., Towler, C., Wang, P., Williams, S. L., Zhang, J.-H., & LaMarche, M. J.
- Affiliations
- Global Discovery Chemistry, ‡Oncology Disease Area, §Center for Proteomic Chemistry, ∥Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, and ⊥Chemical and Pharmaceutical Profiling, Novartis Pharmaceuticals, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
- Novartis Institutes for BioMedical Research (CH)
- Corresponding author
- LaMarche, Matthew J.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-07-12
- Volume
- 59
- Issue
- 17
- Pages
- 7773-7782
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2475259576
- Cited by
- 298
- References
- 37
- Citations by year
- 2026: 24 · 2025: 34 · 2024: 39 · 2023: 32 · 2022: 36 · 2021: 33 · 2020: 32 · 2019: 27 · 2018: 25 · 2017: 14 · 2016: 2
- FWCI
- 12.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.osti.gov
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (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 inhibition, protein tyrosine phosphatase, SHP099, PTPN11, MAPK signaling, PD-1/PD-L1, allosteric binding pocket, structure-based drug design, oral bioavailability, small molecule inhibitors, cancer therapy
- MeSH terms
- Administration, Oral, Allosteric Regulation, Allosteric Site, Animals, Antineoplastic Agents, Female, Humans, Male, Mice, Inbred C57BL, Mice, Nude, Models, Molecular, Neoplasm Transplantation, Piperidines, Protein Conformation, Pyrazines, Pyrimidines, Structure-Activity Relationship, Drug Design, Crystallography, X-Ray, Cell Line, Tumor, Protein Tyrosine Phosphatase, Non-Receptor Type 11, High-Throughput Screening Assays, Heterografts
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