Discovery of the First Examples of Threonine Tyrosine Kinase PROTAC Degraders
The first examples of threonine tyrosine kinase (TTK) PROTACs were designed and synthesized. Two of the most potent molecules, 8e and 8j, demonstrated strong TTK degradation in COLO-205 human colorectal cancer cells with DC50 values of 1.7 and 3.1 nM, respectively. Proteasome-mediated degradation by...
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| Veröffentlicht in: | Journal of medicinal chemistry 2022-02, Vol.65 (3), p.2313-2328 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 65 |
| creator | Lu, Jibu Huang, Yongjun Huang, Jing He, Rui Huang, Minhao Lu, Xiaoyun Xu, Yong Zhou, Fengtao Zhang, Zhang Ding, Ke |
| description | The first examples of threonine tyrosine kinase (TTK) PROTACs were designed and synthesized. Two of the most potent molecules, 8e and 8j, demonstrated strong TTK degradation in COLO-205 human colorectal cancer cells with DC50 values of 1.7 and 3.1 nM, respectively. Proteasome-mediated degradation by the compounds could last for approximately 8 h after washout. The degraders 8e and 8j demonstrated improved antiproliferative activities comparing with the structurally similar inhibitor counterparts 8q and 8r. Degraders 8e and 8j also demonstrated reasonable PK profiles and exhibited potent target degradation and in vivo anticancer efficacy in a xenograft mouse model of COLO-205 human colorectal cancer cells upon i.p. administration. |
| doi_str_mv | 10.1021/acs.jmedchem.1c01768 |
| format | Article |
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Two of the most potent molecules, 8e and 8j, demonstrated strong TTK degradation in COLO-205 human colorectal cancer cells with DC50 values of 1.7 and 3.1 nM, respectively. Proteasome-mediated degradation by the compounds could last for approximately 8 h after washout. The degraders 8e and 8j demonstrated improved antiproliferative activities comparing with the structurally similar inhibitor counterparts 8q and 8r. Degraders 8e and 8j also demonstrated reasonable PK profiles and exhibited potent target degradation and in vivo anticancer efficacy in a xenograft mouse model of COLO-205 human colorectal cancer cells upon i.p. administration.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c01768</identifier><identifier>PMID: 35084180</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Drug Design ; Humans ; Ligands ; Male ; Mice ; Mice, SCID ; Neoplasms - drug therapy ; Proteasome Endopeptidase Complex - metabolism ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use ; Protein-Tyrosine Kinases - chemistry ; Protein-Tyrosine Kinases - metabolism ; Proteolysis - drug effects ; Structure-Activity Relationship ; Transplantation, Heterologous ; Von Hippel-Lindau Tumor Suppressor Protein - chemistry ; Von Hippel-Lindau Tumor Suppressor Protein - metabolism</subject><ispartof>Journal of medicinal chemistry, 2022-02, Vol.65 (3), p.2313-2328</ispartof><rights>2022 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-cd7dc8237c894ce38dca7c5e83dfceeeff3855c5798621790608a8d13ed888a3</citedby><cites>FETCH-LOGICAL-a348t-cd7dc8237c894ce38dca7c5e83dfceeeff3855c5798621790608a8d13ed888a3</cites><orcidid>0000-0001-7931-6873 ; 0000-0003-3601-0246 ; 0000-0001-9016-812X</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.1c01768$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01768$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35084180$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lu, Jibu</creatorcontrib><creatorcontrib>Huang, Yongjun</creatorcontrib><creatorcontrib>Huang, Jing</creatorcontrib><creatorcontrib>He, Rui</creatorcontrib><creatorcontrib>Huang, Minhao</creatorcontrib><creatorcontrib>Lu, Xiaoyun</creatorcontrib><creatorcontrib>Xu, Yong</creatorcontrib><creatorcontrib>Zhou, Fengtao</creatorcontrib><creatorcontrib>Zhang, Zhang</creatorcontrib><creatorcontrib>Ding, Ke</creatorcontrib><title>Discovery of the First Examples of Threonine Tyrosine Kinase PROTAC Degraders</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The first examples of threonine tyrosine kinase (TTK) PROTACs were designed and synthesized. Two of the most potent molecules, 8e and 8j, demonstrated strong TTK degradation in COLO-205 human colorectal cancer cells with DC50 values of 1.7 and 3.1 nM, respectively. Proteasome-mediated degradation by the compounds could last for approximately 8 h after washout. The degraders 8e and 8j demonstrated improved antiproliferative activities comparing with the structurally similar inhibitor counterparts 8q and 8r. Degraders 8e and 8j also demonstrated reasonable PK profiles and exhibited potent target degradation and in vivo anticancer efficacy in a xenograft mouse model of COLO-205 human colorectal cancer cells upon i.p. administration.</description><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Ligands</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Neoplasms - drug therapy</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Protein-Tyrosine Kinases - chemistry</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Proteolysis - drug effects</subject><subject>Structure-Activity Relationship</subject><subject>Transplantation, Heterologous</subject><subject>Von Hippel-Lindau Tumor Suppressor Protein - chemistry</subject><subject>Von Hippel-Lindau Tumor Suppressor Protein - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtPwzAQhC0EoqXwDxDKkUvK2s7DPVZ9AAJUhHK3jL2hqfIodoLov8ehLUdOtuyZ2Z2PkGsKYwqM3intxpsKjV5jNaYaaJqIEzKkMYMwEhCdkiEAYyFLGB-QC-c2AMAp4-dkwGMQERUwJC_zwunmC-0uaPKgXWOwLKxrg8W3qrYluv41W1ts6qLGINvZxvWXp6JWDoPXt1U2nQVz_LDKoHWX5CxXpcOrwzki2XKRzR7C59X942z6HCoeiTbUJjVaMJ5qMYk0cmG0SnWMgptcI2KecxHHOk4nImE0nUACQglDORohhOIjcruP3drms0PXysq3wLJUNTadk31lziGOqJdGe6n2mzuLudzaolJ2JynInqP0HOWRozxw9Labw4Tu3f_9mY7gvAD2gl9709na9_0_8weebIHM</recordid><startdate>20220210</startdate><enddate>20220210</enddate><creator>Lu, Jibu</creator><creator>Huang, Yongjun</creator><creator>Huang, Jing</creator><creator>He, Rui</creator><creator>Huang, Minhao</creator><creator>Lu, Xiaoyun</creator><creator>Xu, Yong</creator><creator>Zhou, Fengtao</creator><creator>Zhang, Zhang</creator><creator>Ding, Ke</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><orcidid>https://orcid.org/0000-0001-7931-6873</orcidid><orcidid>https://orcid.org/0000-0003-3601-0246</orcidid><orcidid>https://orcid.org/0000-0001-9016-812X</orcidid></search><sort><creationdate>20220210</creationdate><title>Discovery of the First Examples of Threonine Tyrosine Kinase PROTAC Degraders</title><author>Lu, Jibu ; Huang, Yongjun ; Huang, Jing ; He, Rui ; Huang, Minhao ; Lu, Xiaoyun ; Xu, Yong ; Zhou, Fengtao ; Zhang, Zhang ; Ding, Ke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-cd7dc8237c894ce38dca7c5e83dfceeeff3855c5798621790608a8d13ed888a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Drug Design</topic><topic>Humans</topic><topic>Ligands</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, SCID</topic><topic>Neoplasms - drug therapy</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Protein-Tyrosine Kinases - chemistry</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Proteolysis - drug effects</topic><topic>Structure-Activity Relationship</topic><topic>Transplantation, Heterologous</topic><topic>Von Hippel-Lindau Tumor Suppressor Protein - chemistry</topic><topic>Von Hippel-Lindau Tumor Suppressor Protein - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lu, Jibu</creatorcontrib><creatorcontrib>Huang, Yongjun</creatorcontrib><creatorcontrib>Huang, Jing</creatorcontrib><creatorcontrib>He, Rui</creatorcontrib><creatorcontrib>Huang, Minhao</creatorcontrib><creatorcontrib>Lu, Xiaoyun</creatorcontrib><creatorcontrib>Xu, Yong</creatorcontrib><creatorcontrib>Zhou, Fengtao</creatorcontrib><creatorcontrib>Zhang, Zhang</creatorcontrib><creatorcontrib>Ding, Ke</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lu, Jibu</au><au>Huang, Yongjun</au><au>Huang, Jing</au><au>He, Rui</au><au>Huang, Minhao</au><au>Lu, Xiaoyun</au><au>Xu, Yong</au><au>Zhou, Fengtao</au><au>Zhang, Zhang</au><au>Ding, Ke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of the First Examples of Threonine Tyrosine Kinase PROTAC Degraders</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2022-02-10</date><risdate>2022</risdate><volume>65</volume><issue>3</issue><spage>2313</spage><epage>2328</epage><pages>2313-2328</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The first examples of threonine tyrosine kinase (TTK) PROTACs were designed and synthesized. Two of the most potent molecules, 8e and 8j, demonstrated strong TTK degradation in COLO-205 human colorectal cancer cells with DC50 values of 1.7 and 3.1 nM, respectively. Proteasome-mediated degradation by the compounds could last for approximately 8 h after washout. The degraders 8e and 8j demonstrated improved antiproliferative activities comparing with the structurally similar inhibitor counterparts 8q and 8r. 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| subjects | Animals Cell Line, Tumor Cell Proliferation - drug effects Drug Design Humans Ligands Male Mice Mice, SCID Neoplasms - drug therapy Proteasome Endopeptidase Complex - metabolism Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Protein-Tyrosine Kinases - chemistry Protein-Tyrosine Kinases - metabolism Proteolysis - drug effects Structure-Activity Relationship Transplantation, Heterologous Von Hippel-Lindau Tumor Suppressor Protein - chemistry Von Hippel-Lindau Tumor Suppressor Protein - metabolism |
| title | Discovery of the First Examples of Threonine Tyrosine Kinase PROTAC Degraders |
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