Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Nov;84(7):1395-1410.
doi: 10.1002/ddr.22100. Epub 2023 Aug 15.

Allosteric modulation of SHP2: Quest from known to unknown

Ning Wang  1   2 , Shilin Zhu  3 , Dan Lv  1   2   4 , Yajun Wang  3 , Muhammad B Khawar  1   2   5 , Haibo Sun  1   2
Affiliations
Review

Allosteric modulation of SHP2: Quest from known to unknown

Ning Wang et al. Drug Dev Res. 2023 Nov.

Abstract

Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) is a key regulatory factor in the cell cycle and its activating mutations play an important role in the development of various cancers, making it an important target for antitumor drugs. Due to the highly conserved amino acid sequence and positively charged nature of the active site of SHP2, it is difficult to discover inhibitors with high affinity for the catalytic site of SHP2 and sufficient cell permeability, making it considered an "undruggable" target. However, the discovery of allosteric regulation mechanisms provides new opportunities for transforming undruggable targets into druggable ones. Given the limitations of orthosteric inhibitors, SHP2 allosteric inhibitors have become a more selective and safer research direction. In this review, we elucidate the oncogenic mechanism of SHP2 and summarize the discovery methods of SHP2 allosteric inhibitors, providing new strategies for the design and improvement of SHP2 allosteric inhibitors.

Keywords: SHP2's inhibitors; allosteric drugs; allosteric regulation; protein tyrosine phosphatase.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

References

REFERENCES

    1. Adeniji, E. A., Olotu, F. A., & Soliman, M. E. S. (2019). Exploring the lapse in druggability: Sequence analysis, structural dynamics and binding site characterization of K-RasG12C variant, a feasible oncotherapeutics target. Anti-Cancer Agents in Medicinal Chemistry, 18(11), 1540-1550. https://doi.org/10.2174/1871520618666180718110231
    1. Agazie, Y. M., & Hayman, M. J. (2003). Molecular mechanism for a role of SHP2 in epidermal growth factor receptor signaling. Molecular and Cellular Biology, 23(21), 7875-7886. https://doi.org/10.1128/mcb.23.21.7875-7886.2003
    1. Alonso, A., Sasin, J., Bottini, N., Friedberg, I., Friedberg, I., Osterman, A., Godzik, A., Hunter, T., Dixon, J., & Mustelin, T. (2004). Protein tyrosine phosphatases in the human genome. Cell, 117(6), 699-711. https://doi.org/10.1016/j.cell.2004.05.018
    1. Astl, L., Tse, A., & Verkhivker, G. M. (2019). Interrogating regulatory mechanisms in signaling proteins by allosteric inhibitors and activators: a dynamic view through the lens of residue interaction networks. Advances in Experimental Medicine and Biology, 1163, 187-223. https://doi.org/10.1007/978-981-13-8719-7_9
    1. Bard-Chapeau, E. A., Li, S., Ding, J., Zhang, S. S., Zhu, H. H., Princen, F., Fang, D. D., Han, T., Bailly-Maitre, B., Poli, V., Varki, N. M., Wang, H., & Feng, G.-S. (2011). Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer Cell, 19(5), 629-639. https://doi.org/10.1016/j.ccr.2011.03.023

Publication types

MeSH terms

Substances

LinkOut - more resources