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Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex

文献类型：期刊论文

作者Zhang, Zemin8; Li, Yuanqing6,7; Yang, Jie5; Li, Jiacheng6; Lin, Xiongqiang8; Liu, Ting8; Yang, Shiling5; Lin, Jin8; Xue, Shengyu6,7; Yu, Jiamin6,7
刊名NATURE COMMUNICATIONS
出版日期2024-08-01
卷号15期号:1页码:13
DOI10.1038/s41467-024-50642-0
通讯作者Ding, Hong(hding@simm.ac.cn) ; Luo, Cheng(cluo@simm.ac.cn) ; Lin, Hua(hlin@fjnu.edu.cn)
英文摘要Protein-protein interactions (PPIs) stabilization with molecular glues plays a crucial role in drug discovery, albeit with significant challenges. In this study, we propose a dual-site approach, targeting the PPI region and its dynamic surroundings. We conduct molecular dynamics simulations to identify critical sites on the PPI that stabilize the cyclin-dependent kinase 12 - DNA damage-binding protein 1 (CDK12-DDB1) complex, resulting in further cyclin K degradation. This exploration leads to the creation of LL-K12-18, a dual-site molecular glue, which enhances the glue properties to augment degradation kinetics and efficiency. Notably, LL-K12-18 demonstrates strong inhibition of gene transcription and anti-proliferative effects in tumor cells, showing significant potency improvements in MDA-MB-231 (88-fold) and MDA-MB-468 cells (307-fold) when compared to its precursor compound SR-4835. These findings underscore the potential of dual-site approaches in disrupting CDK12 function and offer a structural insight-based framework for the design of cyclin K molecular glues. Protein-protein interactions (PPIs) stabilization with molecular glues plays a crucial role in drug discovery. Here, the authors propose a dual-site approach for the design of clyclin K molecular glues, targeting the PPI region and its dynamic surroundings, and report a dual-site molecular glue for the cyclin-dependent kinase 12 - DNA damage-binding protein 1 complex, resulting in further cyclin K degradation.
WOS关键词DESIGN ; UBIQUITINATION ; FLEXIBILITY ; DEGRADATION ; TARGET
资助项目National Natural Science Foundation of China (National Science Foundation of China)[2022YFC3400500] ; National Natural Science Foundation of China (National Science Foundation of China)[2023YFD1800102] ; National Natural Science Foundation of China (National Science Foundation of China)[2022YFC2804800] ; National Key R&D Program of China[22377013] ; National Key R&D Program of China[81821005] ; National Key R&D Program of China[U23A20108] ; National Key R&D Program of China[92253303] ; National Natural Science Foundation of China[2021J01203] ; Fujian Provincial Natural Science Foundation[SKLDR-2023-KF-07] ; State Key Laboratory of Drug Research[YDZX20233100004032] ; Science and Technology Commission of Shanghai Municipality ; National Multidisciplinary Innovation Team of Traditional Chinese Medicine[ZYYCXTD202004] ; National Administration of Traditional Chinese Medicine[GZNL2023A02012] ; Major Program of Guangzhou National Laboratory[2019B090904008] ; Major Program of Guangzhou National Laboratory[2021B0909050003] ; High-level New RD Institute ; Department of Science and Technology of Guangdong Province[LY23H190002] ; Zhejiang Provincial Natural Science Foundation of China[2023HIAS-Y023] ; Hangzhou Institute for Advanced Study
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001285103000021
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/312673]  
专题新药研究国家重点实验室
通讯作者Ding, Hong; Luo, Cheng; Lin, Hua
作者单位1.Guizhou Med Univ, Sch Pharm, State Key Lab Funct & Applicat Med Plants, Guiyang, Peoples R China
2.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Peoples R China
4.Univ Chinese Acad Sci, Beijing, Peoples R China
5.Fujian Normal Univ, Key Lab Microbial Pathogenesis & Intervent Fujian, Key Lab Innate Immune Biol Fujian Prov, Biomed Res Ctr South China,Coll Life Sci, Fuzhou, Peoples R China
6.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China
7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
8.Fujian Med Univ, Sch Pharm, Fuzhou, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Zemin,Li, Yuanqing,Yang, Jie,et al. Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex[J]. NATURE COMMUNICATIONS,2024,15(1):13.
APA Zhang, Zemin.,Li, Yuanqing.,Yang, Jie.,Li, Jiacheng.,Lin, Xiongqiang.,...&Lin, Hua.(2024).Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex.NATURE COMMUNICATIONS,15(1),13.
MLA Zhang, Zemin,et al."Dual-site molecular glues for enhancing protein-protein interactions of the CDK12-DDB1 complex".NATURE COMMUNICATIONS 15.1(2024):13.

入库方式： OAI收割

来源：上海药物研究所

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