Discovery of LL-K8-22 : A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex
The CDK8-cyclin C complex is an important anti-tumor target, but unlike CDK8, cyclin C remains undruggable. Modulators regulating cyclin C activity directly are still under development. Here, a series of hydrophobic tagging-based degraders of the CDK8-cyclin C complex were designed, synthesized, and evaluated to identify the first dual degrader, LL-K8-22, which induced selective and synchronous degradation of CDK8 and cyclin C. Proteomic and immunoblot studies exhibited that LL-K8-22 significantly degraded CDK8 without reducing CDK19 and did not degrade other cyclin proteins except cyclin C. Moreover, LL-K8-22 showed enhanced anti-proliferative effects over its parental molecule, BI-1347, with potency increased by 5-fold in MDA-MB-468 cells. LL-K8-22 exhibited more pronounced effects on CDK8-cyclin C downstream signaling than BI-1347, suppressing STAT1 phosphorylation more persistently. RNA-sequencing analysis revealed that LL-K8-22 inhibited E2F- and MYC-driven carcinogenic transcriptional programs. Overall, LL-K8-22 is the first-in-class degrader of cyclin C and would be useful for studying the unknown functions of cyclin C.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
Journal of medicinal chemistry - 66(2023), 7 vom: 13. Apr., Seite 4932-4951 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Mingyu [VerfasserIn] |
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| Links: |
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| Themen: |
BI-1347 |
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| Anmerkungen: |
Date Completed 22.01.2024 Date Revised 22.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.2c02045 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM35436104X |
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| 100 | 1 | |a Wang, Mingyu |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of LL-K8-22 |b A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The CDK8-cyclin C complex is an important anti-tumor target, but unlike CDK8, cyclin C remains undruggable. Modulators regulating cyclin C activity directly are still under development. Here, a series of hydrophobic tagging-based degraders of the CDK8-cyclin C complex were designed, synthesized, and evaluated to identify the first dual degrader, LL-K8-22, which induced selective and synchronous degradation of CDK8 and cyclin C. Proteomic and immunoblot studies exhibited that LL-K8-22 significantly degraded CDK8 without reducing CDK19 and did not degrade other cyclin proteins except cyclin C. Moreover, LL-K8-22 showed enhanced anti-proliferative effects over its parental molecule, BI-1347, with potency increased by 5-fold in MDA-MB-468 cells. LL-K8-22 exhibited more pronounced effects on CDK8-cyclin C downstream signaling than BI-1347, suppressing STAT1 phosphorylation more persistently. RNA-sequencing analysis revealed that LL-K8-22 inhibited E2F- and MYC-driven carcinogenic transcriptional programs. Overall, LL-K8-22 is the first-in-class degrader of cyclin C and would be useful for studying the unknown functions of cyclin C | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Lin, Rongkun |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jiacheng |e verfasserin |4 aut | |
| 700 | 1 | |a Suo, Yuying |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Liping |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Liyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Ni, Yicheng |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Ziqun |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Hu |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Hua |e verfasserin |4 aut | |
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