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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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+ Show Author Affiliations
  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:
Journal Article: 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.
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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. https://doi.org/10.1021/acs.jmedchem.6b00680
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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. https://doi.org/10.1021/acs.jmedchem.6b00680. https://www.osti.gov/servlets/purl/1404987.
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@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},
url = {https://www.osti.gov/biblio/1404987}, journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 17,
volume = 59,
place = {United States},
year = {2016},
month = {6}
}
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Journal Article:
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Publisher's Version of Record
https://doi.org/10.1021/acs.jmedchem.6b00680
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Works referencing / citing this record:

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Structure based design of selective SHP2 inhibitors by De novo design, synthesis and biological evaluation
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Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2
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Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition
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RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers
journal, August 2018

Inducing and exploiting vulnerabilities for the treatment of liver cancer
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Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition
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SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo
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Biologically active marine natural products and their molecular targets discovered using a chemical genetics approach
journal, January 2020

Identification and structure–function analyses of an allosteric inhibitor of the tyrosine phosphatase PTPN22
journal, April 2019

Targeting PDGFRα-activated glioblastoma through specific inhibition of SHP-2–mediated signaling
journal, June 2019

Synthetic lethality of TNK2 inhibition in PTPN11-mutant leukemia
journal, July 2018

Strategies for monitoring and combating resistance to combination kinase inhibitors for cancer therapy
journal, April 2017

Proteinaceous Regulators and Inhibitors of Protein Tyrosine Phosphatases
journal, February 2018

Design, Synthesis, and In Vitro Activity of Pyrazine Compounds
journal, December 2019

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