Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs
Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK‐degrading Proteolysis Targeting...
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| creator | Law, Robert P. Nunes, Joao Chung, Chun‐wa Bantscheff, Marcus Buda, Karol Dai, Han Evans, John P. Flinders, Adam Klimaszewska, Diana Lewis, Antonia J. Muelbaier, Marcel Scott‐Stevens, Paul Stacey, Peter Tame, Christopher J. Watt, Gillian F. Zinn, Nico Queisser, Markus A. Harling, John D. Benowitz, Andrew B. |
| description | Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK‐degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS‐4718. X‐ray crystallography revealed the molecular basis of the highly cooperative FAK‐GSK215‐VHL ternary complex, and GSK215 showed differentiated in‐vitro pharmacology compared to VS‐4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long‐lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK‐degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.
A PROTAC with an unusually short linker potently degrades focal adhesion kinase (FAK). SPR and X‐ray crystallography revealed a highly cooperative FAK‐PROTAC‐VCB ternary complex, and FAK degradation showed enhanced effects on 3D cell growth compared to FAK inhibitors. In mice, GSK215 induced rapid and sustained degradation of FAK with a profound PK/PD disconnect. |
| doi_str_mv | 10.1002/anie.202109237 |
| format | Article |
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A PROTAC with an unusually short linker potently degrades focal adhesion kinase (FAK). SPR and X‐ray crystallography revealed a highly cooperative FAK‐PROTAC‐VCB ternary complex, and FAK degradation showed enhanced effects on 3D cell growth compared to FAK inhibitors. In mice, GSK215 induced rapid and sustained degradation of FAK with a profound PK/PD disconnect.</description><edition>International ed. in English</edition><identifier>ISSN: 1433-7851</identifier><identifier>EISSN: 1521-3773</identifier><identifier>DOI: 10.1002/anie.202109237</identifier><language>eng</language><publisher>Weinheim: Wiley Subscription Services, Inc</publisher><subject>cancer ; Clinical trials ; Crystallography ; Degradation ; drug design ; Focal adhesion kinase ; In vivo methods and tests ; Kinases ; medicinal chemistry ; Metastases ; Pharmacology ; protein degradation ; Proteolysis ; proteolysis-targeting chimeras (PROTACs) ; Tumors ; Ubiquitin-protein ligase</subject><ispartof>Angewandte Chemie International Edition, 2021-10, Vol.60 (43), p.23327-23334</ispartof><rights>2021 Wiley‐VCH GmbH</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3507-1e06bfec17d3348ed2c4e2377417b402a8527075c012bfa85d22e16c6eaddfad3</citedby><cites>FETCH-LOGICAL-c3507-1e06bfec17d3348ed2c4e2377417b402a8527075c012bfa85d22e16c6eaddfad3</cites><orcidid>0000-0003-3602-324X ; 0000-0002-2480-3110 ; 0000-0002-3879-3160 ; 0000-0003-3592-5751 ; 0000-0002-8343-8977 ; 0000-0002-3368-3827 ; 0000-0001-9312-0498 ; 0000-0002-9913-605X ; 0000-0002-2585-4585</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fanie.202109237$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fanie.202109237$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids></links><search><creatorcontrib>Law, Robert P.</creatorcontrib><creatorcontrib>Nunes, Joao</creatorcontrib><creatorcontrib>Chung, Chun‐wa</creatorcontrib><creatorcontrib>Bantscheff, Marcus</creatorcontrib><creatorcontrib>Buda, Karol</creatorcontrib><creatorcontrib>Dai, Han</creatorcontrib><creatorcontrib>Evans, John P.</creatorcontrib><creatorcontrib>Flinders, Adam</creatorcontrib><creatorcontrib>Klimaszewska, Diana</creatorcontrib><creatorcontrib>Lewis, Antonia J.</creatorcontrib><creatorcontrib>Muelbaier, Marcel</creatorcontrib><creatorcontrib>Scott‐Stevens, Paul</creatorcontrib><creatorcontrib>Stacey, Peter</creatorcontrib><creatorcontrib>Tame, Christopher J.</creatorcontrib><creatorcontrib>Watt, Gillian F.</creatorcontrib><creatorcontrib>Zinn, Nico</creatorcontrib><creatorcontrib>Queisser, Markus A.</creatorcontrib><creatorcontrib>Harling, John D.</creatorcontrib><creatorcontrib>Benowitz, Andrew B.</creatorcontrib><title>Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs</title><title>Angewandte Chemie International Edition</title><description>Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK‐degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS‐4718. X‐ray crystallography revealed the molecular basis of the highly cooperative FAK‐GSK215‐VHL ternary complex, and GSK215 showed differentiated in‐vitro pharmacology compared to VS‐4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long‐lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK‐degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.
A PROTAC with an unusually short linker potently degrades focal adhesion kinase (FAK). SPR and X‐ray crystallography revealed a highly cooperative FAK‐PROTAC‐VCB ternary complex, and FAK degradation showed enhanced effects on 3D cell growth compared to FAK inhibitors. In mice, GSK215 induced rapid and sustained degradation of FAK with a profound PK/PD disconnect.</description><subject>cancer</subject><subject>Clinical trials</subject><subject>Crystallography</subject><subject>Degradation</subject><subject>drug design</subject><subject>Focal adhesion kinase</subject><subject>In vivo methods and tests</subject><subject>Kinases</subject><subject>medicinal chemistry</subject><subject>Metastases</subject><subject>Pharmacology</subject><subject>protein degradation</subject><subject>Proteolysis</subject><subject>proteolysis-targeting chimeras (PROTACs)</subject><subject>Tumors</subject><subject>Ubiquitin-protein ligase</subject><issn>1433-7851</issn><issn>1521-3773</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNqFkM1OAjEUhRujiYhuXU_ixs1g_2Y6LMkAQiRiDK6bMr0DJcMUW8DMzkfwGX0SSzCauHF1f_Kdm3MPQtcEdwjG9E7VBjoUU4K7lIkT1CIJJTETgp2GnjMWiywh5-jC-1XgswynLTTpG1_YPbgmUrWO8qVyqtiCM15tja0jW0Yjs1hWTZRbuwEXtnuIhr2Hz_ePPiyc0qZeRE_P01kv95forFSVh6vv2kYvw8EsH8WT6f04703igiVYxARwOi-hIEIzxjPQtOAQLAtOxJxjqrKECiySAhM6L8OkKQWSFikorUulWRvdHu9unH3dgd_KdfgCqkrVYHde0iRlnPJE4IDe_EFXdufq4C5QIQGeCtoNVOdIFc5676CUG2fWyjWSYHkIVx7ClT_hBkH3KHgzFTT_0LL3OB78ar8AIQZ9bQ</recordid><startdate>20211018</startdate><enddate>20211018</enddate><creator>Law, Robert P.</creator><creator>Nunes, Joao</creator><creator>Chung, Chun‐wa</creator><creator>Bantscheff, Marcus</creator><creator>Buda, Karol</creator><creator>Dai, Han</creator><creator>Evans, John P.</creator><creator>Flinders, Adam</creator><creator>Klimaszewska, Diana</creator><creator>Lewis, Antonia J.</creator><creator>Muelbaier, Marcel</creator><creator>Scott‐Stevens, Paul</creator><creator>Stacey, Peter</creator><creator>Tame, Christopher J.</creator><creator>Watt, Gillian F.</creator><creator>Zinn, Nico</creator><creator>Queisser, Markus A.</creator><creator>Harling, John D.</creator><creator>Benowitz, Andrew B.</creator><general>Wiley Subscription Services, Inc</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3602-324X</orcidid><orcidid>https://orcid.org/0000-0002-2480-3110</orcidid><orcidid>https://orcid.org/0000-0002-3879-3160</orcidid><orcidid>https://orcid.org/0000-0003-3592-5751</orcidid><orcidid>https://orcid.org/0000-0002-8343-8977</orcidid><orcidid>https://orcid.org/0000-0002-3368-3827</orcidid><orcidid>https://orcid.org/0000-0001-9312-0498</orcidid><orcidid>https://orcid.org/0000-0002-9913-605X</orcidid><orcidid>https://orcid.org/0000-0002-2585-4585</orcidid></search><sort><creationdate>20211018</creationdate><title>Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs</title><author>Law, Robert P. ; Nunes, Joao ; Chung, Chun‐wa ; Bantscheff, Marcus ; Buda, Karol ; Dai, Han ; Evans, John P. ; Flinders, Adam ; Klimaszewska, Diana ; Lewis, Antonia J. ; Muelbaier, Marcel ; Scott‐Stevens, Paul ; Stacey, Peter ; Tame, Christopher J. ; Watt, Gillian F. ; Zinn, Nico ; Queisser, Markus A. ; Harling, John D. ; Benowitz, Andrew B.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3507-1e06bfec17d3348ed2c4e2377417b402a8527075c012bfa85d22e16c6eaddfad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>cancer</topic><topic>Clinical trials</topic><topic>Crystallography</topic><topic>Degradation</topic><topic>drug design</topic><topic>Focal adhesion kinase</topic><topic>In vivo methods and tests</topic><topic>Kinases</topic><topic>medicinal chemistry</topic><topic>Metastases</topic><topic>Pharmacology</topic><topic>protein degradation</topic><topic>Proteolysis</topic><topic>proteolysis-targeting chimeras (PROTACs)</topic><topic>Tumors</topic><topic>Ubiquitin-protein ligase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Law, Robert P.</creatorcontrib><creatorcontrib>Nunes, Joao</creatorcontrib><creatorcontrib>Chung, Chun‐wa</creatorcontrib><creatorcontrib>Bantscheff, Marcus</creatorcontrib><creatorcontrib>Buda, Karol</creatorcontrib><creatorcontrib>Dai, Han</creatorcontrib><creatorcontrib>Evans, John P.</creatorcontrib><creatorcontrib>Flinders, Adam</creatorcontrib><creatorcontrib>Klimaszewska, Diana</creatorcontrib><creatorcontrib>Lewis, Antonia J.</creatorcontrib><creatorcontrib>Muelbaier, Marcel</creatorcontrib><creatorcontrib>Scott‐Stevens, Paul</creatorcontrib><creatorcontrib>Stacey, Peter</creatorcontrib><creatorcontrib>Tame, Christopher J.</creatorcontrib><creatorcontrib>Watt, Gillian F.</creatorcontrib><creatorcontrib>Zinn, Nico</creatorcontrib><creatorcontrib>Queisser, Markus A.</creatorcontrib><creatorcontrib>Harling, John D.</creatorcontrib><creatorcontrib>Benowitz, Andrew B.</creatorcontrib><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Angewandte Chemie International Edition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Law, Robert P.</au><au>Nunes, Joao</au><au>Chung, Chun‐wa</au><au>Bantscheff, Marcus</au><au>Buda, Karol</au><au>Dai, Han</au><au>Evans, John P.</au><au>Flinders, Adam</au><au>Klimaszewska, Diana</au><au>Lewis, Antonia J.</au><au>Muelbaier, Marcel</au><au>Scott‐Stevens, Paul</au><au>Stacey, Peter</au><au>Tame, Christopher J.</au><au>Watt, Gillian F.</au><au>Zinn, Nico</au><au>Queisser, Markus A.</au><au>Harling, John D.</au><au>Benowitz, Andrew B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs</atitle><jtitle>Angewandte Chemie International Edition</jtitle><date>2021-10-18</date><risdate>2021</risdate><volume>60</volume><issue>43</issue><spage>23327</spage><epage>23334</epage><pages>23327-23334</pages><issn>1433-7851</issn><eissn>1521-3773</eissn><abstract>Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK‐degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS‐4718. X‐ray crystallography revealed the molecular basis of the highly cooperative FAK‐GSK215‐VHL ternary complex, and GSK215 showed differentiated in‐vitro pharmacology compared to VS‐4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long‐lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK‐degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.
A PROTAC with an unusually short linker potently degrades focal adhesion kinase (FAK). SPR and X‐ray crystallography revealed a highly cooperative FAK‐PROTAC‐VCB ternary complex, and FAK degradation showed enhanced effects on 3D cell growth compared to FAK inhibitors. In mice, GSK215 induced rapid and sustained degradation of FAK with a profound PK/PD disconnect.</abstract><cop>Weinheim</cop><pub>Wiley Subscription Services, Inc</pub><doi>10.1002/anie.202109237</doi><tpages>8</tpages><edition>International ed. in English</edition><orcidid>https://orcid.org/0000-0003-3602-324X</orcidid><orcidid>https://orcid.org/0000-0002-2480-3110</orcidid><orcidid>https://orcid.org/0000-0002-3879-3160</orcidid><orcidid>https://orcid.org/0000-0003-3592-5751</orcidid><orcidid>https://orcid.org/0000-0002-8343-8977</orcidid><orcidid>https://orcid.org/0000-0002-3368-3827</orcidid><orcidid>https://orcid.org/0000-0001-9312-0498</orcidid><orcidid>https://orcid.org/0000-0002-9913-605X</orcidid><orcidid>https://orcid.org/0000-0002-2585-4585</orcidid></addata></record> |
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| subjects | cancer Clinical trials Crystallography Degradation drug design Focal adhesion kinase In vivo methods and tests Kinases medicinal chemistry Metastases Pharmacology protein degradation Proteolysis proteolysis-targeting chimeras (PROTACs) Tumors Ubiquitin-protein ligase |
| title | Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs |
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