skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases

Abstract

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase1. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma1, 2, 3, 4, 5. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway2, 3. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways6, 7. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy8, 9. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, thesemore » data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; « less
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1404986
Resource Type:
Journal Article
Journal Name:
Nature (London)
Additional Journal Information:
Journal Volume: 535; Journal Issue: 7610; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Chen, Ying-Nan P., LaMarche, Matthew J., Chan, Ho Man, Fekkes, Peter, Garcia-Fortanet, Jorge, Acker, Michael G., Antonakos, Brandon, Chen, Christine Hiu-Tung, Chen, Zhouliang, Cooke, Vesselina G., Dobson, Jason R., Deng, Zhan, Fei, Feng, Firestone, Brant, Fodor, Michelle, Fridrich, Cary, Gao, Hui, Grunenfelder, Denise, Hao, Huai-Xiang, Jacob, Jaison, Ho, Samuel, Hsiao, Kathy, Kang, Zhao B., Karki, Rajesh, Kato, Mitsunori, Larrow, Jay, La Bonte, Laura R., Lenoir, Francois, Liu, Gang, Liu, Shumei, Majumdar, Dyuti, Meyer, Matthew J., Palermo, Mark, Perez, Lawrence, Pu, Minying, Price, Edmund, Quinn, Christopher, Shakya, Subarna, Shultz, Michael D., Slisz, Joanna, Venkatesan, Kavitha, Wang, Ping, Warmuth, Markus, Williams, Sarah, Yang, Guizhi, Yuan, Jing, Zhang, Ji-Hu, Zhu, Ping, Ramsey, Timothy, Keen, Nicholas J., Sellers, William R., Stams, Travis, and Fortin, Pascal D. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. United States: N. p., 2016. Web. doi:10.1038/nature18621.
Chen, Ying-Nan P., LaMarche, Matthew J., Chan, Ho Man, Fekkes, Peter, Garcia-Fortanet, Jorge, Acker, Michael G., Antonakos, Brandon, Chen, Christine Hiu-Tung, Chen, Zhouliang, Cooke, Vesselina G., Dobson, Jason R., Deng, Zhan, Fei, Feng, Firestone, Brant, Fodor, Michelle, Fridrich, Cary, Gao, Hui, Grunenfelder, Denise, Hao, Huai-Xiang, Jacob, Jaison, Ho, Samuel, Hsiao, Kathy, Kang, Zhao B., Karki, Rajesh, Kato, Mitsunori, Larrow, Jay, La Bonte, Laura R., Lenoir, Francois, Liu, Gang, Liu, Shumei, Majumdar, Dyuti, Meyer, Matthew J., Palermo, Mark, Perez, Lawrence, Pu, Minying, Price, Edmund, Quinn, Christopher, Shakya, Subarna, Shultz, Michael D., Slisz, Joanna, Venkatesan, Kavitha, Wang, Ping, Warmuth, Markus, Williams, Sarah, Yang, Guizhi, Yuan, Jing, Zhang, Ji-Hu, Zhu, Ping, Ramsey, Timothy, Keen, Nicholas J., Sellers, William R., Stams, Travis, & Fortin, Pascal D. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. United States. https://doi.org/10.1038/nature18621
Chen, Ying-Nan P., LaMarche, Matthew J., Chan, Ho Man, Fekkes, Peter, Garcia-Fortanet, Jorge, Acker, Michael G., Antonakos, Brandon, Chen, Christine Hiu-Tung, Chen, Zhouliang, Cooke, Vesselina G., Dobson, Jason R., Deng, Zhan, Fei, Feng, Firestone, Brant, Fodor, Michelle, Fridrich, Cary, Gao, Hui, Grunenfelder, Denise, Hao, Huai-Xiang, Jacob, Jaison, Ho, Samuel, Hsiao, Kathy, Kang, Zhao B., Karki, Rajesh, Kato, Mitsunori, Larrow, Jay, La Bonte, Laura R., Lenoir, Francois, Liu, Gang, Liu, Shumei, Majumdar, Dyuti, Meyer, Matthew J., Palermo, Mark, Perez, Lawrence, Pu, Minying, Price, Edmund, Quinn, Christopher, Shakya, Subarna, Shultz, Michael D., Slisz, Joanna, Venkatesan, Kavitha, Wang, Ping, Warmuth, Markus, Williams, Sarah, Yang, Guizhi, Yuan, Jing, Zhang, Ji-Hu, Zhu, Ping, Ramsey, Timothy, Keen, Nicholas J., Sellers, William R., Stams, Travis, and Fortin, Pascal D. Wed . "Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases". United States. https://doi.org/10.1038/nature18621.
@article{osti_1404986,
title = {Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases},
author = {Chen, Ying-Nan P. and LaMarche, Matthew J. and Chan, Ho Man and Fekkes, Peter and Garcia-Fortanet, Jorge and Acker, Michael G. and Antonakos, Brandon and Chen, Christine Hiu-Tung and Chen, Zhouliang and Cooke, Vesselina G. and Dobson, Jason R. and Deng, Zhan and Fei, Feng and Firestone, Brant and Fodor, Michelle and Fridrich, Cary and Gao, Hui and Grunenfelder, Denise and Hao, Huai-Xiang and Jacob, Jaison and Ho, Samuel and Hsiao, Kathy and Kang, Zhao B. and Karki, Rajesh and Kato, Mitsunori and Larrow, Jay and La Bonte, Laura R. and Lenoir, Francois and Liu, Gang and Liu, Shumei and Majumdar, Dyuti and Meyer, Matthew J. and Palermo, Mark and Perez, Lawrence and Pu, Minying and Price, Edmund and Quinn, Christopher and Shakya, Subarna and Shultz, Michael D. and Slisz, Joanna and Venkatesan, Kavitha and Wang, Ping and Warmuth, Markus and Williams, Sarah and Yang, Guizhi and Yuan, Jing and Zhang, Ji-Hu and Zhu, Ping and Ramsey, Timothy and Keen, Nicholas J. and Sellers, William R. and Stams, Travis and Fortin, Pascal D.},
abstractNote = {The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase1. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma1, 2, 3, 4, 5. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway2, 3. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways6, 7. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy8, 9. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.},
doi = {10.1038/nature18621},
url = {https://www.osti.gov/biblio/1404986}, journal = {Nature (London)},
issn = {0028-0836},
number = 7610,
volume = 535,
place = {United States},
year = {2016},
month = {6}
}