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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. https://doi.org/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. https://doi.org/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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Works referenced in this record:

Crystal Structure of the Tyrosine Phosphatase SHP-2
journal, February 1998


Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2
journal, March 1998


Potent Stimulation of SH-PTP2 Phosphatase Activity by Simultaneous Occupancy of Both SH2 Domains
journal, February 1995

  • Pluskey, Scott; Wandless, Thomas J.; Walsh, Christopher T.
  • Journal of Biological Chemistry, Vol. 270, Issue 7
  • DOI: 10.1074/jbc.270.7.2897

PTPN11 Is a Central Node in Intrinsic and Acquired Resistance to Targeted Cancer Drugs
journal, September 2015


Src-homology 2 domain-containing tyrosine phosphatase 2 promotes oral cancer invasion and metastasis
journal, June 2014


The ‘Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling
journal, June 2003


PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase
journal, October 2006


Protein tyrosine phosphatase function: the substrate perspective
journal, January 2007

  • Tiganis, Tony; Bennett, Anton M.
  • Biochemical Journal, Vol. 402, Issue 1
  • DOI: 10.1042/BJ20061548

Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis
journal, November 2015

  • Bunda, Severa; Burrell, Kelly; Heir, Pardeep
  • Nature Communications, Vol. 6, Issue 1
  • DOI: 10.1038/ncomms9859

Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome
journal, November 2001

  • Tartaglia, Marco; Mehler, Ernest L.; Goldberg, Rosalie
  • Nature Genetics, Vol. 29, Issue 4
  • DOI: 10.1038/ng772

Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia
journal, April 2003

  • Tartaglia, Marco; Niemeyer, Charlotte M.; Fragale, Alessandra
  • Nature Genetics, Vol. 34, Issue 2
  • DOI: 10.1038/ng1156

The tyrosine phosphatase Shp2 (PTPN11) in cancer
journal, February 2008

  • Chan, Gordon; Kalaitzidis, Demetrios; Neel, Benjamin G.
  • Cancer and Metastasis Reviews, Vol. 27, Issue 2
  • DOI: 10.1007/s10555-008-9126-y

Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors
journal, January 2008


PD-1/SHP-2 Inhibits Tc1/Th1 Phenotypic Responses and the Activation of T Cells in the Tumor Microenvironment
journal, December 2014


Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer
journal, June 2012

  • Topalian, Suzanne L.; Hodi, F. Stephen; Brahmer, Julie R.
  • New England Journal of Medicine, Vol. 366, Issue 26
  • DOI: 10.1056/NEJMoa1200690

Clinical Significance of Programmed Death-1 Ligand-1 and Programmed Death-1 Ligand-2 Expression in Human Esophageal Cancer
journal, April 2005


Targeting protein tyrosine phosphatase SHP2 for therapeutic intervention
journal, August 2014

  • Butterworth, Sam; Overduin, Michael; Barr, Alastair J.
  • Future Medicinal Chemistry, Vol. 6, Issue 12
  • DOI: 10.4155/fmc.14.88

Targeting Protein Tyrosine Phosphatases for Anticancer Drug Discovery
journal, June 2010

  • M. Scott, Latanya; R. Lawrence, Harshani; M. Sebti, Said
  • Current Pharmaceutical Design, Vol. 16, Issue 16
  • DOI: 10.2174/138161210791209027

Salicylic Acid Based Small Molecule Inhibitor for the Oncogenic Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2)
journal, February 2010

  • Zhang, Xian; He, Yantao; Liu, Sijiu
  • Journal of Medicinal Chemistry, Vol. 53, Issue 6
  • DOI: 10.1021/jm901645u

Therapeutic Potential of Targeting the Oncogenic SHP2 Phosphatase
journal, July 2014

  • Zeng, Li-Fan; Zhang, Ruo-Yu; Yu, Zhi-Hong
  • Journal of Medicinal Chemistry, Vol. 57, Issue 15
  • DOI: 10.1021/jm5006176

Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction
journal, January 2014

  • Gilmartin, Aidan G.; Faitg, Thomas H.; Richter, Mark
  • Nature Chemical Biology, Vol. 10, Issue 3
  • DOI: 10.1038/nchembio.1427

Rational design of allosteric-inhibition sites in classical protein tyrosine phosphatases
journal, June 2015

  • Chio, Cynthia M.; Yu, Xiaoling; Bishop, Anthony C.
  • Bioorganic & Medicinal Chemistry, Vol. 23, Issue 12
  • DOI: 10.1016/j.bmc.2015.03.027

Selective Detection of Allosteric Phosphatase Inhibitors
journal, April 2013

  • Schneider, Ralf; Beumer, Claudia; Simard, Jeffrey R.
  • Journal of the American Chemical Society, Vol. 135, Issue 18
  • DOI: 10.1021/ja4030484

Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases
journal, June 2016

  • Chen, Ying-Nan P.; LaMarche, Matthew J.; Chan, Ho Man
  • Nature, Vol. 535, Issue 7610
  • DOI: 10.1038/nature18621

Fluorogenic Substrates Based on Fluorinated Umbelliferones for Continuous Assays of Phosphatases and β-Galactosidases
journal, August 1999

  • Gee, Kyle R.; Sun, Wei-Chuan; Bhalgat, Mahesh K.
  • Analytical Biochemistry, Vol. 273, Issue 1
  • DOI: 10.1006/abio.1999.4202

A SHPing tale: Perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail
journal, November 2005


Voltage-gated sodium channels as therapeutic targets
journal, November 2000


The relationship between sodium channel inhibition and anticonvulsant activity in a model of generalised seizure in the rat
journal, July 2009


Bioisosterism:  A Rational Approach in Drug Design
journal, January 1996

  • Patani, George A.; LaVoie, Edmond J.
  • Chemical Reviews, Vol. 96, Issue 8
  • DOI: 10.1021/cr950066q

Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors
journal, October 2013

  • Burger, Matthew T.; Han, Wooseok; Lan, Jiong
  • ACS Medicinal Chemistry Letters, Vol. 4, Issue 12
  • DOI: 10.1021/ml400307j

Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia
journal, November 2010

  • Eriksson, Anna; Höglund, Martin; Lindhagen, Elin
  • Biochemical Pharmacology, Vol. 80, Issue 10
  • DOI: 10.1016/j.bcp.2010.08.002

Design, synthesis, and biological evaluation of aminopyrazine derivatives as inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2)
journal, November 2015

  • Lin, Songnian; Malkani, Sunita; Lombardo, Matthew
  • Bioorganic & Medicinal Chemistry Letters, Vol. 25, Issue 22
  • DOI: 10.1016/j.bmcl.2015.09.016

XDS
journal, January 2010

  • Kabsch, Wolfgang
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
  • DOI: 10.1107/S0907444909047337

Features and development of Coot
journal, March 2010

  • Emsley, P.; Lohkamp, B.; Scott, W. G.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
  • DOI: 10.1107/S0907444910007493

Works referencing / citing this record:

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


Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2
journal, October 2018


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

  • Sang, Youzhou; Hou, Yanli; Cheng, Rongrong
  • Neuro-Oncology, Vol. 21, Issue 11
  • DOI: 10.1093/neuonc/noz107

Critical individual roles of the BCR and FGFR1 kinase domains in BCR‐FGFR1‐driven stem cell leukemia/lymphoma syndrome
journal, October 2019

  • Chong, Yating; Liu, Yun; Lu, Sumin
  • International Journal of Cancer, Vol. 146, Issue 8
  • DOI: 10.1002/ijc.32665

Selective inhibition of leukemia-associated SHP2E69K mutant by the allosteric SHP2 inhibitor SHP099
journal, January 2018


SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo
journal, May 2018

  • Mainardi, Sara; Mulero-Sánchez, Antonio; Prahallad, Anirudh
  • Nature Medicine, Vol. 24, Issue 7
  • DOI: 10.1038/s41591-018-0023-9

Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition
journal, May 2018


Structure based design of selective SHP2 inhibitors by De novo design, synthesis and biological evaluation
journal, July 2019

  • Liu, Wen-Shan; Jin, Wen-Yan; Zhou, Liang
  • Journal of Computer-Aided Molecular Design, Vol. 33, Issue 8
  • DOI: 10.1007/s10822-019-00213-z

SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors
journal, March 2018

  • Dardaei, Leila; Wang, Hui Qin; Singh, Manrose
  • Nature Medicine, Vol. 24, Issue 4
  • DOI: 10.1038/nm.4497

Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition
journal, October 2018

  • LaRochelle, Jonathan R.; Fodor, Michelle; Vemulapalli, Vidyasiri
  • Nature Communications, Vol. 9, Issue 1
  • DOI: 10.1038/s41467-018-06823-9

Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer
journal, December 2018

  • Yuan, Yuncang; Qi, Guoxiang; Shen, Hao
  • International Journal of Cancer, Vol. 144, Issue 7
  • DOI: 10.1002/ijc.31736

Inducing and exploiting vulnerabilities for the treatment of liver cancer
journal, October 2019


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


Interrogating Protein Phosphatases with Chemical Activity Probes
journal, March 2018

  • Casey, Garrett R.; Stains, Cliff I.
  • Chemistry - A European Journal, Vol. 24, Issue 31
  • DOI: 10.1002/chem.201705194

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

  • Parsonidis, Panagiotis; Shaik, Mahammad; Serafeim, Athanasia Panagiota
  • Molecules, Vol. 24, Issue 23
  • DOI: 10.3390/molecules24234389

Biologically active marine natural products and their molecular targets discovered using a chemical genetics approach
journal, January 2020

  • Williams, David E.; Andersen, Raymond J.
  • Natural Product Reports, Vol. 37, Issue 5
  • DOI: 10.1039/c9np00054b

RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers
journal, August 2018

  • Nichols, Robert J.; Haderk, Franziska; Stahlhut, Carlos
  • Nature Cell Biology, Vol. 20, Issue 9
  • DOI: 10.1038/s41556-018-0169-1

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


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

  • Li, Kangshuai; Hou, Xuben; Li, Ruirui
  • Journal of Biological Chemistry, Vol. 294, Issue 21
  • DOI: 10.1074/jbc.ra118.007129