Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors
Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the ra...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2017
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| Online Access: | http://hdl.handle.net/1721.1/108541 https://orcid.org/0000-0001-8855-8647 |
| _version_ | 1826190986051584000 |
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| author | Zhang, Tinghu Kwiatkowski, Nicholas Olson, Calla M Dixon-Clarke, Sarah E Abraham, Brian J Greifenberg, Ann K Ficarro, Scott B Elkins, Jonathan M Liang, Yanke Hannett, Nancy M Manz, Theresa Hao, Mingfeng Bartkowiak, Bartlomiej Greenleaf, Arno L Marto, Jarrod A Geyer, Matthias Bullock, Alex N Gray, Nathanael S Young, Richard A. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Zhang, Tinghu Kwiatkowski, Nicholas Olson, Calla M Dixon-Clarke, Sarah E Abraham, Brian J Greifenberg, Ann K Ficarro, Scott B Elkins, Jonathan M Liang, Yanke Hannett, Nancy M Manz, Theresa Hao, Mingfeng Bartkowiak, Bartlomiej Greenleaf, Arno L Marto, Jarrod A Geyer, Matthias Bullock, Alex N Gray, Nathanael S Young, Richard A. |
| author_sort | Zhang, Tinghu |
| collection | MIT |
| description | Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities. |
| first_indexed | 2024-09-23T08:48:19Z |
| format | Article |
| id | mit-1721.1/108541 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:48:19Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1085412022-09-23T14:41:33Z Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors Zhang, Tinghu Kwiatkowski, Nicholas Olson, Calla M Dixon-Clarke, Sarah E Abraham, Brian J Greifenberg, Ann K Ficarro, Scott B Elkins, Jonathan M Liang, Yanke Hannett, Nancy M Manz, Theresa Hao, Mingfeng Bartkowiak, Bartlomiej Greenleaf, Arno L Marto, Jarrod A Geyer, Matthias Bullock, Alex N Gray, Nathanael S Young, Richard A. Massachusetts Institute of Technology. Department of Biology Young, Richard A Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities. United States. National Institutes of Health (HG002668) United States. National Institutes of Health (CA109901) 2017-05-01T17:59:22Z 2017-05-01T17:59:22Z 2016-08 2015-08 Article http://purl.org/eprint/type/JournalArticle 1552-4450 1552-4469 http://hdl.handle.net/1721.1/108541 Zhang, Tinghu; Kwiatkowski, Nicholas; Olson, Calla M; Dixon-Clarke, Sarah E; Abraham, Brian J; Greifenberg, Ann K and Ficarro, Scott B et al. “Covalent Targeting of Remote Cysteine Residues to Develop CDK12 and CDK13 Inhibitors.” Nature Chemical Biology 12, no. 10 (August 2016): 876–884. © 2016 Nature America, Inc https://orcid.org/0000-0001-8855-8647 en_US http://dx.doi.org/10.1038/nchembio.2166 Nature Chemical Biology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | Zhang, Tinghu Kwiatkowski, Nicholas Olson, Calla M Dixon-Clarke, Sarah E Abraham, Brian J Greifenberg, Ann K Ficarro, Scott B Elkins, Jonathan M Liang, Yanke Hannett, Nancy M Manz, Theresa Hao, Mingfeng Bartkowiak, Bartlomiej Greenleaf, Arno L Marto, Jarrod A Geyer, Matthias Bullock, Alex N Gray, Nathanael S Young, Richard A. Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors |
| title | Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors |
| title_full | Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors |
| title_fullStr | Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors |
| title_full_unstemmed | Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors |
| title_short | Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors |
| title_sort | covalent targeting of remote cysteine residues to develop cdk12 and cdk13 inhibitors |
| url | http://hdl.handle.net/1721.1/108541 https://orcid.org/0000-0001-8855-8647 |
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