Structure-based design, synthesis and biological evaluation of aminopyrazines as highly potent, selective, and cellularly active allosteric SHP2 inhibitors
Abstract
Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) encoded by the proto-oncogene PTPN11 is the first identified non-receptor protein tyrosine phosphatase. SHP2 dysregulation contributes to the pathogenesis of different cancers, making SHP2 a promising therapeutic target for cancer therapy. In this article, we report the structure-guided design based on the well-characterized SHP2 inhibitor SHP099, extensive structure-activity relationship studies (SARs) of aminopyrazines, biochemical characterization and cellular potency. These medicinal chemistry efforts lead to the discovery of the lead compound TK-453, which potently inhibits SHP2 (SHP2 WT IC 50 = 0.023 μM, ΔTm = 7.01 °C) in a reversible and noncompetitive manner. TK-453 exhibits high selectivity over SHP2 PTP, SHP1 and PTP1B, and may bind at the "tunnel" allosteric site of SHP2 as SHP099. As the key pharmacophore, the aminopyrazine scaffold not only reorganizes the cationic-π stacking interaction with R111 via the novel hydrogen bond interaction between the S atom of thioether linker and T219, but also mediates a hydrogen bond with E250. In vitro studies indicate that TK-453 inhibits proliferation of HeLa, KYSE-70 and THP-1 cells moderately and induces apoptosis of Hela cells. Further mechanistic studies suggest that TK-453 can decrease the phosphorylation levels of AKT and Erk1/2 in HeLa and KYSE-70 cells. Collectively, TK-453 is a highly potent, selective, and cellularly active allosteric SHP2 inhibitor that modulates the phosphorylation of SHP2-mediated AKT and Erk cell signaling pathways by inhibiting the phosphatase activity of SHP2.
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TK-453 exhibited a notable capacity to inhibit protease activities of SHP2WT with an IC50 value of 0.023 nM, outperforming its impact on SHP2-related proteins (SHP2E76K, SHP2PTP) as well as their homologs (SHP1 and PTP1B).
“Moreover, TK-453 exhibited a notable capacity to inhibit protease activities of SHP2WT with an IC50 value of 0.023 nM, outperforming its impact on SHP2-related proteins (SHP2E76K, SHP2PTP) as well as their homologs (SHP1 and PTP1B).293”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [293]
TK-453 (Kd = 150 nM) is a selective SHP2 metastable conformation inhibitor identified by a screening method for the enzymatic activity of SHP2-related proteins developed by Sun's team and Yu's team.
“Sun’s team from Nanjing University and Yu’s team from Zhengzhou University developed a screening method for the enzymatic activity of SHP2-related proteins and identified TK-453 (93) (Kd = 150 nM) as a selective SHP2 metastable conformation inhibitor.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [293]
TK-453 binds to the N-SH2, C-SH2 and PTP structural domains of SHP2 proteins at the interface to stabilize the inactive self-inhibited conformation of SHP2.
“TK-453 binds to the N-SH2, C-SH2 and PTP structural domains of SHP2 proteins at the interface to stabilize the inactive self-inhibited conformation of SHP2.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [293]
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BindingDB Entry 50022804: Advances in SHP2 tunnel allosteric inhibitors and bifunctional molecules.
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- Authors
- Tang, K., Zhao, M., Wu, Y.-H., Wu, Q., Wang, S., Dong, Y., Yu, B., Song, Y., & Liu, H.-M.
- Affiliations
- Zhengzhou University (CN)
- Corresponding author
- Yu, Bin
- Song, Yihui
- Liu, Hong-Min
- Venue
- European Journal of Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2022-02
- Volume
- 230
- Pages
- 114106
- ISSN
- 0223-5234 (ISSN-L)
- OpenAlex
- W4206740821
- Cited by
- 20
- References
- 63
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 8 · 2023: 3
- FWCI
- 1.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- European Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Science and Technology Innovation Talents in Universities of Henan Province (21HASTIT045)
- National Natural Science Foundation of China (81973177, U21A20416, 31900875, 81773562)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- SHP2 inhibitors, aminopyrazine, allosteric inhibition, SHP099, structure-activity relationship, protein tyrosine phosphatase, PTPN11, cancer therapy, Akt phosphorylation, ERK1/2 phosphorylation, apoptosis, HeLa cells, cellular potency, hydrogen bonding
- MeSH terms
- Allosteric Site, Enzyme Inhibitors, HeLa Cells, Humans, Phosphorylation, Pyrazines, Structure-Activity Relationship, Protein Tyrosine Phosphatase, Non-Receptor Type 11
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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