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Discovery of LL-K8-22: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex

文献类型：期刊论文

作者Wang, Mingyu1,4; Lin, Rongkun2; Li, Jiacheng1,4; Suo, Yuying1,4; Gao, Jing3; Liu, Liping1,4; Zhou, Liyuan6; Ni, Yicheng6; Yang, Ziqun4,7; Zheng, Jie4,7
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-04-13
卷号66期号:7页码:4932-4951
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c020454932J
通讯作者Zhou, Hu(zhouhu@simm.ac.cn) ; Luo, Cheng(cluo@simm.ac.cn) ; Lin, Hua(hlin@fjnu.edu.cn)
英文摘要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.
WOS关键词DEPENDENT KINASE 8 ; BETA-CATENIN ; TRANSCRIPTIONAL ACTIVATION ; MEDIATOR COMPLEX ; CANCER ; CDK8 ; DEGRADATION ; PROGRESSION ; ELONGATION ; EXPRESSION
资助项目National Centre for Protein Science Shanghai (Protein Expression and Purification system) ; National Key RAMP;D Program of China[2022YFC3400500] ; National Key RAMP;D Program of China[2021ZD0203900] ; Fujian Provincial Natural Science Foundation[2021J01203] ; State Key Laboratory of Drug Research[SIMM2105KF-07] ; National Key Reseach and Development Program[2020YFA0509000] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[92253303] ; National Multidisciplinary Innovation Team of Traditional Chinese Medicine ; National Administration of Traditional Chinese Medicine[ZYYCXTD- 202004] ; High-level New RD Institute[2019B090904008] ; High-level New RD Institute[2021B0909050003] ; Department of Science and Technology of Guangdong Province
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000984699400001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/306572]  
专题新药研究国家重点实验室
通讯作者Zhou, Hu; Luo, Cheng; Lin, Hua
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Fujian Med Univ, Sch Pharm, Fuzhou 350122, Peoples R China
3.Fujian Normal Univ, Coll Life Sci, Biomed Res Ctr South China, Fuzhou 350117, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Zhongshan Inst Drug Discovery, Zhongshan 528437, Peoples R China
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Immunol Dis, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Mingyu,Lin, Rongkun,Li, Jiacheng,et al. Discovery of LL-K8-22: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(7):4932-4951.
APA Wang, Mingyu.,Lin, Rongkun.,Li, Jiacheng.,Suo, Yuying.,Gao, Jing.,...&Lin, Hua.(2023).Discovery of LL-K8-22: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex.JOURNAL OF MEDICINAL CHEMISTRY,66(7),4932-4951.
MLA Wang, Mingyu,et al."Discovery of LL-K8-22: A Selective, Durable, and Small-Molecule Degrader of the CDK8-Cyclin C Complex".JOURNAL OF MEDICINAL CHEMISTRY 66.7(2023):4932-4951.

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来源：上海药物研究所

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