The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma
Abstract CDK12 is a transcriptional cyclin-dependent kinase (CDK) that interacts with cyclin K to regulate different aspects of gene expression. The CDK12-cyclin K complex phosphorylates several substrates, including RNA polymerase II (Pol II), and thereby regulates transcription elongation, RNA spl...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-12-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01754-x |
| _version_ | 1797388524945670144 |
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| author | Thibault Houles Jonathan Boucher Geneviève Lavoie Graham MacLeod Sichun Lin Stephane Angers Philippe P. Roux |
| author_facet | Thibault Houles Jonathan Boucher Geneviève Lavoie Graham MacLeod Sichun Lin Stephane Angers Philippe P. Roux |
| author_sort | Thibault Houles |
| collection | DOAJ |
| description | Abstract CDK12 is a transcriptional cyclin-dependent kinase (CDK) that interacts with cyclin K to regulate different aspects of gene expression. The CDK12-cyclin K complex phosphorylates several substrates, including RNA polymerase II (Pol II), and thereby regulates transcription elongation, RNA splicing, as well as cleavage and polyadenylation. Because of its implication in cancer, including breast cancer and melanoma, multiple pharmacological inhibitors of CDK12 have been identified to date, including THZ531 and SR-4835. While both CDK12 inhibitors affect Poll II phosphorylation, we found that SR-4835 uniquely promotes cyclin K degradation via the proteasome. Using loss-of-function genetic screening, we found that SR-4835 cytotoxicity depends on a functional CUL4-RBX1-DDB1 ubiquitin ligase complex. Consistent with this, we show that DDB1 is required for cyclin K degradation, and that SR-4835 promotes DDB1 interaction with the CDK12-cyclin K complex. Docking studies and structure-activity relationship analyses of SR-4835 revealed the importance of the benzimidazole side-chain in molecular glue activity. Together, our results indicate that SR-4835 acts as a molecular glue that recruits the CDK12-cyclin K complex to the CUL4-RBX1-DDB1 ubiquitin ligase complex to target cyclin K for degradation. |
| first_indexed | 2024-03-08T22:41:06Z |
| format | Article |
| id | doaj.art-29852213a0ff4f3898e31bb9afc0393f |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-08T22:41:06Z |
| publishDate | 2023-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-29852213a0ff4f3898e31bb9afc0393f2023-12-17T12:07:05ZengNature Publishing GroupCell Death Discovery2058-77162023-12-01911910.1038/s41420-023-01754-xThe CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanomaThibault Houles0Jonathan Boucher1Geneviève Lavoie2Graham MacLeod3Sichun Lin4Stephane Angers5Philippe P. Roux6Institute for Research in Immunology and Cancer (IRIC), Université de MontréalInstitute for Research in Immunology and Cancer (IRIC), Université de MontréalInstitute for Research in Immunology and Cancer (IRIC), Université de MontréalDonnelly Centre for Cellular & Biomolecular Research, Temerty Faculty of Medicine, University of TorontoDonnelly Centre for Cellular & Biomolecular Research, Temerty Faculty of Medicine, University of TorontoDonnelly Centre for Cellular & Biomolecular Research, Temerty Faculty of Medicine, University of TorontoInstitute for Research in Immunology and Cancer (IRIC), Université de MontréalAbstract CDK12 is a transcriptional cyclin-dependent kinase (CDK) that interacts with cyclin K to regulate different aspects of gene expression. The CDK12-cyclin K complex phosphorylates several substrates, including RNA polymerase II (Pol II), and thereby regulates transcription elongation, RNA splicing, as well as cleavage and polyadenylation. Because of its implication in cancer, including breast cancer and melanoma, multiple pharmacological inhibitors of CDK12 have been identified to date, including THZ531 and SR-4835. While both CDK12 inhibitors affect Poll II phosphorylation, we found that SR-4835 uniquely promotes cyclin K degradation via the proteasome. Using loss-of-function genetic screening, we found that SR-4835 cytotoxicity depends on a functional CUL4-RBX1-DDB1 ubiquitin ligase complex. Consistent with this, we show that DDB1 is required for cyclin K degradation, and that SR-4835 promotes DDB1 interaction with the CDK12-cyclin K complex. Docking studies and structure-activity relationship analyses of SR-4835 revealed the importance of the benzimidazole side-chain in molecular glue activity. Together, our results indicate that SR-4835 acts as a molecular glue that recruits the CDK12-cyclin K complex to the CUL4-RBX1-DDB1 ubiquitin ligase complex to target cyclin K for degradation.https://doi.org/10.1038/s41420-023-01754-x |
| spellingShingle | Thibault Houles Jonathan Boucher Geneviève Lavoie Graham MacLeod Sichun Lin Stephane Angers Philippe P. Roux The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma Cell Death Discovery |
| title | The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma |
| title_full | The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma |
| title_fullStr | The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma |
| title_full_unstemmed | The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma |
| title_short | The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma |
| title_sort | cdk12 inhibitor sr 4835 functions as a molecular glue that promotes cyclin k degradation in melanoma |
| url | https://doi.org/10.1038/s41420-023-01754-x |
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