A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P‑Loop Conformation
STK17B is a member of the death-associated protein kinase family and has been genetically linked to the development of diverse diseases. However, the role of STK17B in normal and disease pathology is poorly defined. Here, we present the discovery of thieno[3,2-d] pyrimidine SGC-STK17B-1 (11s), a hi...
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| Veröffentlicht in: | Journal of medicinal chemistry 2020-12, Vol.63 (23), p.14626-14646 |
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| creator | Picado, Alfredo Chaikuad, Apirat Wells, Carrow I Shrestha, Safal Zuercher, William J Pickett, Julie E Kwarcinski, Frank E Sinha, Parvathi de Silva, Chandi S Zutshi, Reena Liu, Shubin Kannan, Natarajan Knapp, Stefan Drewry, David H Willson, Timothy M |
| description | STK17B is a member of the death-associated protein kinase family and has been genetically linked to the development of diverse diseases. However, the role of STK17B in normal and disease pathology is poorly defined. Here, we present the discovery of thieno[3,2-d] pyrimidine SGC-STK17B-1 (11s), a high-quality chemical probe for this understudied “dark” kinase. 11s is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of 11s and related thieno[3,2-d]pyrimidines bound to STK17B revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor. Molecular dynamic simulations of STK17B revealed the flexibility of the P-loop and a wide range of R41 conformations available to the apo-protein. The isomeric thieno[2,3-d]pyrimidine SGC-STK17B-1N (19g) was identified as a negative control compound. The >100-fold lower activity of 19g on STK17B was attributed to the reduced basicity of its pyrimidine N1. |
| doi_str_mv | 10.1021/acs.jmedchem.0c01174 |
| format | Article |
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However, the role of STK17B in normal and disease pathology is poorly defined. Here, we present the discovery of thieno[3,2-d] pyrimidine SGC-STK17B-1 (11s), a high-quality chemical probe for this understudied “dark” kinase. 11s is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of 11s and related thieno[3,2-d]pyrimidines bound to STK17B revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor. Molecular dynamic simulations of STK17B revealed the flexibility of the P-loop and a wide range of R41 conformations available to the apo-protein. The isomeric thieno[2,3-d]pyrimidine SGC-STK17B-1N (19g) was identified as a negative control compound. The >100-fold lower activity of 19g on STK17B was attributed to the reduced basicity of its pyrimidine N1.</description><identifier>ISSN: 0022-2623</identifier><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.0c01174</identifier><identifier>PMID: 33215924</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Apoptosis Regulatory Proteins - antagonists & inhibitors ; Apoptosis Regulatory Proteins - chemistry ; Apoptosis Regulatory Proteins - metabolism ; Catalytic Domain ; HEK293 Cells ; Humans ; Mice ; Microsomes, Liver - metabolism ; Molecular Dynamics Simulation ; Molecular Structure ; Protein Binding ; Protein Conformation ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - metabolism ; Protein Kinase Inhibitors - pharmacology ; Protein Serine-Threonine Kinases - antagonists & inhibitors ; Protein Serine-Threonine Kinases - chemistry ; Protein Serine-Threonine Kinases - metabolism ; Pyrimidines - chemical synthesis ; Pyrimidines - metabolism ; Pyrimidines - pharmacology ; Structure-Activity Relationship ; Thiophenes - chemical synthesis ; Thiophenes - metabolism ; Thiophenes - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2020-12, Vol.63 (23), p.14626-14646</ispartof><rights>2020 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-c5168252b73db0d94ecaf81ffef81f1004b27d63af6553e126961bb88bc2ca763</citedby><cites>FETCH-LOGICAL-a449t-c5168252b73db0d94ecaf81ffef81f1004b27d63af6553e126961bb88bc2ca763</cites><orcidid>0000-0001-5973-5798 ; 0000-0003-1120-2209 ; 0000-0002-9836-0068 ; 0000-0002-9535-8528 ; 0000-0001-5995-6494 ; 0000-0003-4799-6792 ; 0000-0001-9331-0427 ; 0000-0003-4181-8223</orcidid></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.0c01174$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01174$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33215924$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Picado, Alfredo</creatorcontrib><creatorcontrib>Chaikuad, Apirat</creatorcontrib><creatorcontrib>Wells, Carrow I</creatorcontrib><creatorcontrib>Shrestha, Safal</creatorcontrib><creatorcontrib>Zuercher, William J</creatorcontrib><creatorcontrib>Pickett, Julie E</creatorcontrib><creatorcontrib>Kwarcinski, Frank E</creatorcontrib><creatorcontrib>Sinha, Parvathi</creatorcontrib><creatorcontrib>de Silva, Chandi S</creatorcontrib><creatorcontrib>Zutshi, Reena</creatorcontrib><creatorcontrib>Liu, Shubin</creatorcontrib><creatorcontrib>Kannan, Natarajan</creatorcontrib><creatorcontrib>Knapp, Stefan</creatorcontrib><creatorcontrib>Drewry, David H</creatorcontrib><creatorcontrib>Willson, Timothy M</creatorcontrib><title>A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P‑Loop Conformation</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>STK17B is a member of the death-associated protein kinase family and has been genetically linked to the development of diverse diseases. However, the role of STK17B in normal and disease pathology is poorly defined. Here, we present the discovery of thieno[3,2-d] pyrimidine SGC-STK17B-1 (11s), a high-quality chemical probe for this understudied “dark” kinase. 11s is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of 11s and related thieno[3,2-d]pyrimidines bound to STK17B revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor. Molecular dynamic simulations of STK17B revealed the flexibility of the P-loop and a wide range of R41 conformations available to the apo-protein. The isomeric thieno[2,3-d]pyrimidine SGC-STK17B-1N (19g) was identified as a negative control compound. The >100-fold lower activity of 19g on STK17B was attributed to the reduced basicity of its pyrimidine N1.</description><subject>Animals</subject><subject>Apoptosis Regulatory Proteins - antagonists & inhibitors</subject><subject>Apoptosis Regulatory Proteins - chemistry</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Catalytic Domain</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Mice</subject><subject>Microsomes, Liver - metabolism</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular Structure</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - metabolism</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein Serine-Threonine Kinases - chemistry</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - metabolism</subject><subject>Pyrimidines - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Thiophenes - chemical synthesis</subject><subject>Thiophenes - metabolism</subject><subject>Thiophenes - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1uEzEUhS1ERUPhDRDyks0E_41nskEqKaVVIxGp7dryeO40LjN2sD1B2fUVeEWeBKdJK9iwuZauz_l8fQ9C7yiZUsLoR23i9H6A1qxgmBJDKK3ECzShJSOFqIl4iSaEMFYwyfgxeh3jPSGEU8ZfoWPOGS1nTEzQz1M8zwBrdI-XwTeAOx_wmQ7f8ZV1OgK-vrmi1Wd8BsFuIOLLFPHSJ3Bmi7Vr8YW9W-Fr6MEku7Fpi9Mq-DH3NL519scIePn74dfC-zWee5fhg07WuzfoqNN9hLeH8wTdnn-5mV8Ui29fL-eni0ILMUuFKamsWcmaircNaWcCjO5q2nWwq5QQ0bCqlVx3siw5UCZnkjZNXTeGGV1JfoI-7bnrsdktC1wKulfrYAcdtsprq_69cXal7vxGVTWVjPIM-HAABJ9_E5MabDTQ99qBH6NiQvI8h6yqLBV7qQk-xgDd8zOUqF1mKmemnjJTh8yy7f3fIz6bnkLKArIXPNr9GFze2P-ZfwB6RKgX</recordid><startdate>20201210</startdate><enddate>20201210</enddate><creator>Picado, Alfredo</creator><creator>Chaikuad, Apirat</creator><creator>Wells, Carrow I</creator><creator>Shrestha, Safal</creator><creator>Zuercher, William J</creator><creator>Pickett, Julie E</creator><creator>Kwarcinski, Frank E</creator><creator>Sinha, Parvathi</creator><creator>de Silva, Chandi S</creator><creator>Zutshi, Reena</creator><creator>Liu, Shubin</creator><creator>Kannan, Natarajan</creator><creator>Knapp, Stefan</creator><creator>Drewry, David H</creator><creator>Willson, Timothy M</creator><general>American Chemical Society</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>5PM</scope><orcidid>https://orcid.org/0000-0001-5973-5798</orcidid><orcidid>https://orcid.org/0000-0003-1120-2209</orcidid><orcidid>https://orcid.org/0000-0002-9836-0068</orcidid><orcidid>https://orcid.org/0000-0002-9535-8528</orcidid><orcidid>https://orcid.org/0000-0001-5995-6494</orcidid><orcidid>https://orcid.org/0000-0003-4799-6792</orcidid><orcidid>https://orcid.org/0000-0001-9331-0427</orcidid><orcidid>https://orcid.org/0000-0003-4181-8223</orcidid></search><sort><creationdate>20201210</creationdate><title>A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P‑Loop Conformation</title><author>Picado, Alfredo ; Chaikuad, Apirat ; Wells, Carrow I ; Shrestha, Safal ; Zuercher, William J ; Pickett, Julie E ; Kwarcinski, Frank E ; Sinha, Parvathi ; de Silva, Chandi S ; Zutshi, Reena ; Liu, Shubin ; Kannan, Natarajan ; Knapp, Stefan ; Drewry, David H ; Willson, Timothy M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-c5168252b73db0d94ecaf81ffef81f1004b27d63af6553e126961bb88bc2ca763</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Apoptosis Regulatory Proteins - antagonists & inhibitors</topic><topic>Apoptosis Regulatory Proteins - chemistry</topic><topic>Apoptosis Regulatory Proteins - metabolism</topic><topic>Catalytic Domain</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Mice</topic><topic>Microsomes, Liver - metabolism</topic><topic>Molecular Dynamics Simulation</topic><topic>Molecular Structure</topic><topic>Protein Binding</topic><topic>Protein Conformation</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - metabolism</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein Serine-Threonine Kinases - chemistry</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - metabolism</topic><topic>Pyrimidines - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Thiophenes - chemical synthesis</topic><topic>Thiophenes - metabolism</topic><topic>Thiophenes - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Picado, Alfredo</creatorcontrib><creatorcontrib>Chaikuad, Apirat</creatorcontrib><creatorcontrib>Wells, Carrow I</creatorcontrib><creatorcontrib>Shrestha, Safal</creatorcontrib><creatorcontrib>Zuercher, William J</creatorcontrib><creatorcontrib>Pickett, Julie E</creatorcontrib><creatorcontrib>Kwarcinski, Frank E</creatorcontrib><creatorcontrib>Sinha, Parvathi</creatorcontrib><creatorcontrib>de Silva, Chandi S</creatorcontrib><creatorcontrib>Zutshi, Reena</creatorcontrib><creatorcontrib>Liu, Shubin</creatorcontrib><creatorcontrib>Kannan, Natarajan</creatorcontrib><creatorcontrib>Knapp, Stefan</creatorcontrib><creatorcontrib>Drewry, David H</creatorcontrib><creatorcontrib>Willson, Timothy M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Picado, Alfredo</au><au>Chaikuad, Apirat</au><au>Wells, Carrow I</au><au>Shrestha, Safal</au><au>Zuercher, William J</au><au>Pickett, Julie E</au><au>Kwarcinski, Frank E</au><au>Sinha, Parvathi</au><au>de Silva, Chandi S</au><au>Zutshi, Reena</au><au>Liu, Shubin</au><au>Kannan, Natarajan</au><au>Knapp, Stefan</au><au>Drewry, David H</au><au>Willson, Timothy M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P‑Loop Conformation</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2020-12-10</date><risdate>2020</risdate><volume>63</volume><issue>23</issue><spage>14626</spage><epage>14646</epage><pages>14626-14646</pages><issn>0022-2623</issn><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>STK17B is a member of the death-associated protein kinase family and has been genetically linked to the development of diverse diseases. However, the role of STK17B in normal and disease pathology is poorly defined. Here, we present the discovery of thieno[3,2-d] pyrimidine SGC-STK17B-1 (11s), a high-quality chemical probe for this understudied “dark” kinase. 11s is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of 11s and related thieno[3,2-d]pyrimidines bound to STK17B revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor. Molecular dynamic simulations of STK17B revealed the flexibility of the P-loop and a wide range of R41 conformations available to the apo-protein. The isomeric thieno[2,3-d]pyrimidine SGC-STK17B-1N (19g) was identified as a negative control compound. The >100-fold lower activity of 19g on STK17B was attributed to the reduced basicity of its pyrimidine N1.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>33215924</pmid><doi>10.1021/acs.jmedchem.0c01174</doi><tpages>21</tpages><orcidid>https://orcid.org/0000-0001-5973-5798</orcidid><orcidid>https://orcid.org/0000-0003-1120-2209</orcidid><orcidid>https://orcid.org/0000-0002-9836-0068</orcidid><orcidid>https://orcid.org/0000-0002-9535-8528</orcidid><orcidid>https://orcid.org/0000-0001-5995-6494</orcidid><orcidid>https://orcid.org/0000-0003-4799-6792</orcidid><orcidid>https://orcid.org/0000-0001-9331-0427</orcidid><orcidid>https://orcid.org/0000-0003-4181-8223</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis Regulatory Proteins - antagonists & inhibitors Apoptosis Regulatory Proteins - chemistry Apoptosis Regulatory Proteins - metabolism Catalytic Domain HEK293 Cells Humans Mice Microsomes, Liver - metabolism Molecular Dynamics Simulation Molecular Structure Protein Binding Protein Conformation Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - metabolism Protein Kinase Inhibitors - pharmacology Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - chemistry Protein Serine-Threonine Kinases - metabolism Pyrimidines - chemical synthesis Pyrimidines - metabolism Pyrimidines - pharmacology Structure-Activity Relationship Thiophenes - chemical synthesis Thiophenes - metabolism Thiophenes - pharmacology |
| title | A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P‑Loop Conformation |
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