Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor
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 wit...
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| Veröffentlicht in: | Journal of medicinal chemistry 2016-09, Vol.59 (17), p.7773-7782 |
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| creator | Garcia Fortanet, Jorge 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 |
| description | 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. 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_str_mv | 10.1021/acs.jmedchem.6b00680 |
| format | Article |
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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. 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.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.6b00680</identifier><identifier>PMID: 27347692</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>60 APPLIED LIFE SCIENCES ; Administration, Oral ; Allosteric Regulation ; Allosteric Site ; amines ; Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Cell Line, Tumor ; conformation ; Crystallography, X-Ray ; Drug Design ; Female ; Heterografts ; High-Throughput Screening Assays ; Humans ; inhibition ; inhibitors ; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY ; Male ; Mice, Inbred C57BL ; Mice, Nude ; Models, Molecular ; Neoplasm Transplantation ; peptides and proteins ; Piperidines - chemical synthesis ; Piperidines - chemistry ; Piperidines - pharmacokinetics ; Piperidines - pharmacology ; Protein Conformation ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - chemistry ; Pyrazines - chemical synthesis ; Pyrazines - chemistry ; Pyrazines - pharmacokinetics ; Pyrazines - pharmacology ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacokinetics ; Pyrimidines - pharmacology ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2016-09, Vol.59 (17), p.7773-7782</ispartof><rights>Copyright © 2016 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a487t-8c5e193c8a3a0b087a65bca7c4f743e53fa79dfaf210e3ec40dbb886bfccd7bb3</citedby><cites>FETCH-LOGICAL-a487t-8c5e193c8a3a0b087a65bca7c4f743e53fa79dfaf210e3ec40dbb886bfccd7bb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.6b00680$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.6b00680$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27347692$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/servlets/purl/1404987$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Garcia Fortanet, Jorge</creatorcontrib><creatorcontrib>Chen, Christine Hiu-Tung</creatorcontrib><creatorcontrib>Chen, Ying-Nan P</creatorcontrib><creatorcontrib>Chen, Zhouliang</creatorcontrib><creatorcontrib>Deng, Zhan</creatorcontrib><creatorcontrib>Firestone, Brant</creatorcontrib><creatorcontrib>Fekkes, Peter</creatorcontrib><creatorcontrib>Fodor, Michelle</creatorcontrib><creatorcontrib>Fortin, Pascal D</creatorcontrib><creatorcontrib>Fridrich, Cary</creatorcontrib><creatorcontrib>Grunenfelder, Denise</creatorcontrib><creatorcontrib>Ho, Samuel</creatorcontrib><creatorcontrib>Kang, Zhao B</creatorcontrib><creatorcontrib>Karki, Rajesh</creatorcontrib><creatorcontrib>Kato, Mitsunori</creatorcontrib><creatorcontrib>Keen, Nick</creatorcontrib><creatorcontrib>LaBonte, Laura R</creatorcontrib><creatorcontrib>Larrow, Jay</creatorcontrib><creatorcontrib>Lenoir, Francois</creatorcontrib><creatorcontrib>Liu, Gang</creatorcontrib><creatorcontrib>Liu, Shumei</creatorcontrib><creatorcontrib>Lombardo, Franco</creatorcontrib><creatorcontrib>Majumdar, Dyuti</creatorcontrib><creatorcontrib>Meyer, Matthew J</creatorcontrib><creatorcontrib>Palermo, Mark</creatorcontrib><creatorcontrib>Perez, Lawrence</creatorcontrib><creatorcontrib>Pu, Minying</creatorcontrib><creatorcontrib>Ramsey, Timothy</creatorcontrib><creatorcontrib>Sellers, William R</creatorcontrib><creatorcontrib>Shultz, Michael D</creatorcontrib><creatorcontrib>Stams, Travis</creatorcontrib><creatorcontrib>Towler, Christopher</creatorcontrib><creatorcontrib>Wang, Ping</creatorcontrib><creatorcontrib>Williams, Sarah L</creatorcontrib><creatorcontrib>Zhang, Ji-Hu</creatorcontrib><creatorcontrib>LaMarche, Matthew J</creatorcontrib><creatorcontrib>Argonne National Laboratory (ANL), Argonne, IL (United States)</creatorcontrib><title>Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>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. 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.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Administration, Oral</subject><subject>Allosteric Regulation</subject><subject>Allosteric Site</subject><subject>amines</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>conformation</subject><subject>Crystallography, X-Ray</subject><subject>Drug Design</subject><subject>Female</subject><subject>Heterografts</subject><subject>High-Throughput Screening Assays</subject><subject>Humans</subject><subject>inhibition</subject><subject>inhibitors</subject><subject>INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY</subject><subject>Male</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Nude</subject><subject>Models, Molecular</subject><subject>Neoplasm Transplantation</subject><subject>peptides and proteins</subject><subject>Piperidines - chemical synthesis</subject><subject>Piperidines - chemistry</subject><subject>Piperidines - pharmacokinetics</subject><subject>Piperidines - pharmacology</subject><subject>Protein Conformation</subject><subject>Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors</subject><subject>Protein Tyrosine Phosphatase, Non-Receptor Type 11 - chemistry</subject><subject>Pyrazines - chemical synthesis</subject><subject>Pyrazines - chemistry</subject><subject>Pyrazines - pharmacokinetics</subject><subject>Pyrazines - pharmacology</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacokinetics</subject><subject>Pyrimidines - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtrGzEUhUVpady0_6AU0VUXGffqMSO5uxDSxhCIIe1aSJorRmE8cqVxIP--Sm1nmZXg6jvnPg4hnxksGXD23fqyfNhi7wfcLjsH0Gl4Qxas5dBIDfItWQBw3vCOizPyoZQHABCMi_fkjCshVbfiC5IvxzGVGXP0dD0N0cU5pommQO9vNvwHXfc4zTFEb091SzdprsULeo8j-jk-4gW1U0_vsh3HJ3odnmkf077QzZDKbrCzLXhyT_kjeRfsWPDT8T0nf35e_766aW7vfq2vLm8bK7WaG-1bZCvhtRUWHGhlu9Z5q7wMSgpsRbBq1QcbOAMU6CX0zmndueB9r5wT5-TrwbfuF03xcUY_-DRNdWjDJMiVVhX6doB2Of3dY5nNNhaP42gnrBsYppkWout4W1F5QH1OpWQMZpfj1uYnw8A8R2JqJOYUiTlGUmVfjh32rv69iE4ZVAAOwH952uepXuV1z38b5Jxk</recordid><startdate>20160908</startdate><enddate>20160908</enddate><creator>Garcia Fortanet, Jorge</creator><creator>Chen, Christine Hiu-Tung</creator><creator>Chen, Ying-Nan P</creator><creator>Chen, Zhouliang</creator><creator>Deng, Zhan</creator><creator>Firestone, Brant</creator><creator>Fekkes, Peter</creator><creator>Fodor, Michelle</creator><creator>Fortin, Pascal D</creator><creator>Fridrich, Cary</creator><creator>Grunenfelder, Denise</creator><creator>Ho, Samuel</creator><creator>Kang, Zhao B</creator><creator>Karki, Rajesh</creator><creator>Kato, Mitsunori</creator><creator>Keen, Nick</creator><creator>LaBonte, Laura R</creator><creator>Larrow, Jay</creator><creator>Lenoir, Francois</creator><creator>Liu, Gang</creator><creator>Liu, Shumei</creator><creator>Lombardo, Franco</creator><creator>Majumdar, Dyuti</creator><creator>Meyer, Matthew J</creator><creator>Palermo, Mark</creator><creator>Perez, Lawrence</creator><creator>Pu, Minying</creator><creator>Ramsey, Timothy</creator><creator>Sellers, William R</creator><creator>Shultz, Michael D</creator><creator>Stams, Travis</creator><creator>Towler, Christopher</creator><creator>Wang, Ping</creator><creator>Williams, Sarah L</creator><creator>Zhang, Ji-Hu</creator><creator>LaMarche, Matthew J</creator><general>American Chemical Society</general><general>American Chemical Society (ACS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>OIOZB</scope><scope>OTOTI</scope></search><sort><creationdate>20160908</creationdate><title>Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor</title><author>Garcia Fortanet, Jorge ; 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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a487t-8c5e193c8a3a0b087a65bca7c4f743e53fa79dfaf210e3ec40dbb886bfccd7bb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Administration, Oral</topic><topic>Allosteric Regulation</topic><topic>Allosteric Site</topic><topic>amines</topic><topic>Animals</topic><topic>Antineoplastic Agents - 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Med. Chem</addtitle><date>2016-09-08</date><risdate>2016</risdate><volume>59</volume><issue>17</issue><spage>7773</spage><epage>7782</epage><pages>7773-7782</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><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. 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.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>27347692</pmid><doi>10.1021/acs.jmedchem.6b00680</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2016-09, Vol.59 (17), p.7773-7782 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_osti_scitechconnect_1404987 |
| source | MEDLINE; American Chemical Society Journals |
| subjects | 60 APPLIED LIFE SCIENCES Administration, Oral Allosteric Regulation Allosteric Site amines Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Cell Line, Tumor conformation Crystallography, X-Ray Drug Design Female Heterografts High-Throughput Screening Assays Humans inhibition inhibitors INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY Male Mice, Inbred C57BL Mice, Nude Models, Molecular Neoplasm Transplantation peptides and proteins Piperidines - chemical synthesis Piperidines - chemistry Piperidines - pharmacokinetics Piperidines - pharmacology Protein Conformation Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors Protein Tyrosine Phosphatase, Non-Receptor Type 11 - chemistry Pyrazines - chemical synthesis Pyrazines - chemistry Pyrazines - pharmacokinetics Pyrazines - pharmacology Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacokinetics Pyrimidines - pharmacology Structure-Activity Relationship |
| title | Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T12%3A32%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_osti_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Allosteric%20Inhibition%20of%20SHP2:%20Identification%20of%20a%20Potent,%20Selective,%20and%20Orally%20Efficacious%20Phosphatase%20Inhibitor&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Garcia%20Fortanet,%20Jorge&rft.aucorp=Argonne%20National%20Laboratory%20(ANL),%20Argonne,%20IL%20(United%20States)&rft.date=2016-09-08&rft.volume=59&rft.issue=17&rft.spage=7773&rft.epage=7782&rft.pages=7773-7782&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/acs.jmedchem.6b00680&rft_dat=%3Cproquest_osti_%3E1818336625%3C/proquest_osti_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1818336625&rft_id=info:pmid/27347692&rfr_iscdi=true |