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Title: Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor

Abstract

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. Furthermore, 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.

Authors:
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  1. Novartis Pharmaceuticals, Cambridge, MA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1404987
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 59; Journal Issue: 17; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES; peptides and proteins; amines; inhibitors; inhibition; conformation

Citation Formats

Fortanet, Jorge Garcia, Chen, Christine Hiu-Tung, Chen, Ying-Nan P., Chen, Zhouliang, Deng, Zhan, Firestone, Brant, Fekkes, Peter, Fodor, Michelle, Fortin, Pascal D., Fridrich, Cary, Grunenfelder, Denise, Ho, Samuel, Kang, Zhao B., Karki, Rajesh, Kato, Mitsunori, Keen, Nick, LaBonte, Laura R., Larrow, Jay, Lenoir, Francois, Liu, Gang, Liu, Shumei, Lombardo, Franco, Majumdar, Dyuti, Meyer, Matthew J., Palermo, Mark, Perez, Lawrence, Pu, Minying, Ramsey, Timothy, Sellers, William R., Shultz, Michael D., Stams, Travis, Towler, Christopher, Wang, Ping, Williams, Sarah L., Zhang, Ji-Hu, and LaMarche, Matthew J. Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor. United States: N. p., 2016. Web. doi:10.1021/acs.jmedchem.6b00680.
Fortanet, Jorge Garcia, Chen, Christine Hiu-Tung, Chen, Ying-Nan P., Chen, Zhouliang, Deng, Zhan, Firestone, Brant, Fekkes, Peter, Fodor, Michelle, Fortin, Pascal D., Fridrich, Cary, Grunenfelder, Denise, Ho, Samuel, Kang, Zhao B., Karki, Rajesh, Kato, Mitsunori, Keen, Nick, LaBonte, Laura R., Larrow, Jay, Lenoir, Francois, Liu, Gang, Liu, Shumei, Lombardo, Franco, Majumdar, Dyuti, Meyer, Matthew J., Palermo, Mark, Perez, Lawrence, Pu, Minying, Ramsey, Timothy, Sellers, William R., Shultz, Michael D., Stams, Travis, Towler, Christopher, Wang, Ping, Williams, Sarah L., Zhang, Ji-Hu, & LaMarche, Matthew J. Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor. United States. doi:10.1021/acs.jmedchem.6b00680.
Fortanet, Jorge Garcia, Chen, Christine Hiu-Tung, Chen, Ying-Nan P., Chen, Zhouliang, Deng, Zhan, Firestone, Brant, Fekkes, Peter, Fodor, Michelle, Fortin, Pascal D., Fridrich, Cary, Grunenfelder, Denise, Ho, Samuel, Kang, Zhao B., Karki, Rajesh, Kato, Mitsunori, Keen, Nick, LaBonte, Laura R., Larrow, Jay, Lenoir, Francois, Liu, Gang, Liu, Shumei, Lombardo, Franco, Majumdar, Dyuti, Meyer, Matthew J., Palermo, Mark, Perez, Lawrence, Pu, Minying, Ramsey, Timothy, Sellers, William R., Shultz, Michael D., Stams, Travis, Towler, Christopher, Wang, Ping, Williams, Sarah L., Zhang, Ji-Hu, and LaMarche, Matthew J. Mon . "Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor". United States. doi:10.1021/acs.jmedchem.6b00680. https://www.osti.gov/servlets/purl/1404987.
@article{osti_1404987,
title = {Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor},
author = {Fortanet, Jorge Garcia and Chen, Christine Hiu-Tung and Chen, Ying-Nan P. and Chen, Zhouliang and Deng, Zhan and Firestone, Brant and Fekkes, Peter and Fodor, Michelle and Fortin, Pascal D. and Fridrich, Cary and Grunenfelder, Denise and Ho, Samuel and Kang, Zhao B. and Karki, Rajesh and Kato, Mitsunori and Keen, Nick and LaBonte, Laura R. and Larrow, Jay and Lenoir, Francois and Liu, Gang and Liu, Shumei and Lombardo, Franco and Majumdar, Dyuti and Meyer, Matthew J. and Palermo, Mark and Perez, Lawrence and Pu, Minying and Ramsey, Timothy and Sellers, William R. and Shultz, Michael D. and Stams, Travis and Towler, Christopher and Wang, Ping and Williams, Sarah L. and Zhang, Ji-Hu and LaMarche, Matthew J.},
abstractNote = {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. Furthermore, 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.},
doi = {10.1021/acs.jmedchem.6b00680},
journal = {Journal of Medicinal Chemistry},
number = 17,
volume = 59,
place = {United States},
year = {2016},
month = {6}
}

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