Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation
Molecular-glue degraders mediate interactions between target proteins and components of the ubiquitin-proteasome system to cause selective protein degradation. Here, we report a new molecular glue HQ461 discovered by high-throughput screening. Using loss-of-function and gain-of-function genetic scre...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/59994 |
| _version_ | 1811181017622380544 |
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| author | Lu Lv Peihao Chen Longzhi Cao Yamei Li Zhi Zeng Yue Cui Qingcui Wu Jiaojiao Li Jian-Hua Wang Meng-Qiu Dong Xiangbing Qi Ting Han |
| author_facet | Lu Lv Peihao Chen Longzhi Cao Yamei Li Zhi Zeng Yue Cui Qingcui Wu Jiaojiao Li Jian-Hua Wang Meng-Qiu Dong Xiangbing Qi Ting Han |
| author_sort | Lu Lv |
| collection | DOAJ |
| description | Molecular-glue degraders mediate interactions between target proteins and components of the ubiquitin-proteasome system to cause selective protein degradation. Here, we report a new molecular glue HQ461 discovered by high-throughput screening. Using loss-of-function and gain-of-function genetic screening in human cancer cells followed by biochemical reconstitution, we show that HQ461 acts by promoting an interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and degradation of CDK12-interacting protein Cyclin K (CCNK). Degradation of CCNK mediated by HQ461 compromised CDK12 function, leading to reduced phosphorylation of a CDK12 substrate, downregulation of DNA damage response genes, and cell death. Structure-activity relationship analysis of HQ461 revealed the importance of a 5-methylthiazol-2-amine pharmacophore and resulted in an HQ461 derivate with improved potency. Our studies reveal a new molecular glue that recruits its target protein directly to DDB1 to bypass the requirement of a substrate-specific receptor, presenting a new strategy for targeted protein degradation. |
| first_indexed | 2024-04-11T09:12:23Z |
| format | Article |
| id | doaj.art-2516480b8dea4d3f9002f19ca4784d02 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:12:23Z |
| publishDate | 2020-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-2516480b8dea4d3f9002f19ca4784d022022-12-22T04:32:28ZengeLife Sciences Publications LtdeLife2050-084X2020-08-01910.7554/eLife.59994Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradationLu Lv0https://orcid.org/0000-0003-2075-8620Peihao Chen1Longzhi Cao2Yamei Li3Zhi Zeng4Yue Cui5Qingcui Wu6Jiaojiao Li7Jian-Hua Wang8Meng-Qiu Dong9https://orcid.org/0000-0002-6094-1182Xiangbing Qi10https://orcid.org/0000-0002-7139-5164Ting Han11https://orcid.org/0000-0003-3168-8699College of Life Sciences, Beijing Normal University, Beijing, China; National Institute of Biological Sciences, Beijing, ChinaNational Institute of Biological Sciences, Beijing, China; School of Life Sciences, Peking University, Beijing, ChinaNational Institute of Biological Sciences, Beijing, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaNational Institute of Biological Sciences, Beijing, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaNational Institute of Biological Sciences, Beijing, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaCollege of Life Sciences, Beijing Normal University, Beijing, China; National Institute of Biological Sciences, Beijing, ChinaNational Institute of Biological Sciences, Beijing, ChinaNational Institute of Biological Sciences, Beijing, ChinaNational Institute of Biological Sciences, Beijing, ChinaNational Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, ChinaNational Institute of Biological Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, ChinaNational Institute of Biological Sciences, Beijing, China; Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, ChinaMolecular-glue degraders mediate interactions between target proteins and components of the ubiquitin-proteasome system to cause selective protein degradation. Here, we report a new molecular glue HQ461 discovered by high-throughput screening. Using loss-of-function and gain-of-function genetic screening in human cancer cells followed by biochemical reconstitution, we show that HQ461 acts by promoting an interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and degradation of CDK12-interacting protein Cyclin K (CCNK). Degradation of CCNK mediated by HQ461 compromised CDK12 function, leading to reduced phosphorylation of a CDK12 substrate, downregulation of DNA damage response genes, and cell death. Structure-activity relationship analysis of HQ461 revealed the importance of a 5-methylthiazol-2-amine pharmacophore and resulted in an HQ461 derivate with improved potency. Our studies reveal a new molecular glue that recruits its target protein directly to DDB1 to bypass the requirement of a substrate-specific receptor, presenting a new strategy for targeted protein degradation.https://elifesciences.org/articles/59994molecular gluetarget identificationtargeted protein degradationCDK12/CCNK |
| spellingShingle | Lu Lv Peihao Chen Longzhi Cao Yamei Li Zhi Zeng Yue Cui Qingcui Wu Jiaojiao Li Jian-Hua Wang Meng-Qiu Dong Xiangbing Qi Ting Han Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation eLife molecular glue target identification targeted protein degradation CDK12/CCNK |
| title | Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation |
| title_full | Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation |
| title_fullStr | Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation |
| title_full_unstemmed | Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation |
| title_short | Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation |
| title_sort | discovery of a molecular glue promoting cdk12 ddb1 interaction to trigger cyclin k degradation |
| topic | molecular glue target identification targeted protein degradation CDK12/CCNK |
| url | https://elifesciences.org/articles/59994 |
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