Discovery of Potent and Selective CDK9 Degraders for Targeting Transcription Regulation in Triple-Negative Breast Cancer

doi:10.1021/acs.jmedchem.1c01350

	Discovery of Potent and Selective CDK9 Degraders for Targeting Transcription Regulation in Triple-Negative Breast Cancer
	Wei, Dan 1,2; Wang, Hanlin 2,3,4; Zeng, Qinghe 1,2; Wang, Wenjing 1,2; Hao, Bingbing 4; Feng, Xule 1; Wang, Peipei 4; Song, Ning 2,4; Kan, Weijuan 4; Huang, Guifang 5
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-10-14
卷号	64 期号:19 页码:14822-14847
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.1c01350
通讯作者	Huang, Ruimin(rmhuang@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Chen, Xiao-Hua(xhchen@simm.ac.cn)
英文摘要	Triple-negative breast cancer (TNBC) is highly aggressive with very limited treatment options due to the lack of efficient targeted therapies and thus still remains clinically challenging. Targeting transcription-associated cyclin-dependent kinases to remodel transcriptional regulation shows great promise in cancer therapy. Herein, we report the synthesis, optimization, and evaluation of new series of heterobifunctional molecules as highly selective and efficacious CDK9 degraders, enabling potent inhibition of TNBC cell growth and rapidly targeted degradation of CDK9. Moreover, the most potent CDK9 degrader (compound 45) induces cell apoptosis in vitro and inhibits tumor growth in the MDA-MB-231 TNBC model. Furthermore, the RNA-seq, immunohistochemistry assays demonstrate that the CDK9 degrader downregulates the downstream targets, such as MYC, at the transcriptional level, resulting apoptosis in TNBC cells. Our work establishes that 45 is a highly potent and efficacious CDK9 degrader for targeting transcription regulation, which represents an effective strategy and great potential as a new targeted therapy for TNBC.
资助项目	National Science Foundation of China (NSFC)[92053106] ; National Science Foundation of China (NSFC)[22177120] ; National Science Foundation of China (NSFC)[91859106] ; National Science Foundation of China (NSFC)[81821005] ; Science and Technology Commission of Shanghai Municipality, China[18431907100] ; Science and Technology Commission of Shanghai Municipality, China[20S11901400] ; Science and Technology Commission of Shanghai Municipality, China[16431902200] ; Science and Technology Commission of Shanghai Municipality, China[21S11907500]
WOS关键词	BET BROMODOMAIN INHIBITORS ; CYCLIN-DEPENDENT KINASES ; SYNTHETIC LETHAL ; RESISTANCE ; PROTACS ; UBIQUITINATION ; DEGRADATION ; PROTEOLYSIS ; ADDICTION ; COMPLEX
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000709633100047
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298686]
专题	中国科学院上海药物研究所
通讯作者	Huang, Ruimin; Li, Jia; Chen, Xiao-Hua
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Fudan Univ, Coll Pharm, Shanghai 201203, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 6.Chinese Acad Sci, Inst Drug Discovery & Dev, Zhongshan Inst Drug Discovery, Zhongshan 528400, Guangdong, Peoples R China 7.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式 GB/T 7714	Wei, Dan,Wang, Hanlin,Zeng, Qinghe,et al. Discovery of Potent and Selective CDK9 Degraders for Targeting Transcription Regulation in Triple-Negative Breast Cancer[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(19):14822-14847.
APA	Wei, Dan.,Wang, Hanlin.,Zeng, Qinghe.,Wang, Wenjing.,Hao, Bingbing.,...&Chen, Xiao-Hua.(2021).Discovery of Potent and Selective CDK9 Degraders for Targeting Transcription Regulation in Triple-Negative Breast Cancer.JOURNAL OF MEDICINAL CHEMISTRY,64(19),14822-14847.
MLA	Wei, Dan,et al."Discovery of Potent and Selective CDK9 Degraders for Targeting Transcription Regulation in Triple-Negative Breast Cancer".JOURNAL OF MEDICINAL CHEMISTRY 64.19(2021):14822-14847.