Discovery of Small-Molecule Degraders of the CDK9-Cyclin T1 Complex for Targeting Transcriptional Addiction in Prostate Cancer

doi:10.1021/acs.jmedchem.2c00257

	Discovery of Small-Molecule Degraders of the CDK9-Cyclin T1 Complex for Targeting Transcriptional Addiction in Prostate Cancer
	Li, Jiacheng 1,3; Liu, Ting 2; Song, Yuanli 2,3,4,5; Wang, Mingyu 1,3; Liu, Liping 1,3; Zhu, Hongwen 3,4,5; Li, Qi 1,3; Lin, Jin 2; Jiang, Hualiang 1,3; Chen, Kaixian 1,3; Zhao, Kehao 8; Wang, Mingliang 1; Zhou, Hu 3,4,5; Lin, Hua 1,6; Luo, Cheng 1,2,3,7
	2022-08-25
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year])
ISSN	0022-2623
EISSN	1520-4804
发表状态	已发表
DOI	10.1021/acs.jmedchem.2c00257
摘要	Aberrant hyperactivation of cyclins results in carcinogenesis and therapy resistance in cancers. Direct degradation of the specific cyclin or cyclin-dependent kinase (CDK)-cyclin complex by small-molecule degraders remains a great challenge. Here, we applied the first application of hydrophobic tagging to induce degradation of CDK9-cyclin T1 heterodimer, which is required to keep productive transcription of oncogenes in cancers. LL-K9-3 was identified as a potent small-molecule degrader of CDK9-cyclin T1. Quantitative and time-resolved proteome profiling exhibited LL-K9-3 induced selective and synchronous degradation of CDK9 and cyclin T1. The expressions of androgen receptor (AR) and cMyc were reduced by LL-K9-3 in 22RV1 cells. LL-K9-3 exhibited enhanced anti-proliferative and pro-apoptotic effects compared with its parental CDK9 inhibitor SNS032 and suppressed downstream signaling of CDK9 and AR more effectively than SNS032. Moreover, LL-K9-3 inhibited AR and Myc-driven oncogenic transcriptional programs and exerted stronger inhibitory effects on several intrinsic target genes of AR than the monomeric CDK9 PROTAC (Thal-SNS032).
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收录类别	SCI ; SCIE ; IC
语种	英语
资助项目	National Key R&D Program of China[2021ZD0203900] ; scientific research innovation program
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000838291400001
出版者	AMER CHEMICAL SOC
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/216441
专题	生命科学与技术学院
通讯作者	Zhou, Hu; Lin, Hua; Luo, Cheng
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Chem Biol, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 2.Fujian Med Univ, Sch Pharm, Fuzhou 350122, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, State Key Lab Drug Res, Shanghai 201203, Peoples R China 6.Fujian Normal Univ, Coll Life Sci, Biomed Res Ctr South China, Fuzhou 350117, Peoples R China 7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 8.Yantai Univ, Minist Educ, Key Lab Mol Pharmacol & Drug Evaluat, Collaborat Innovat Ctr Adv Drug Delivery Syst & Bi, Yantai 264005, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Li, Jiacheng,Liu, Ting,Song, Yuanli,et al. Discovery of Small-Molecule Degraders of the CDK9-Cyclin T1 Complex for Targeting Transcriptional Addiction in Prostate Cancer[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022.
APA	Li, Jiacheng.,Liu, Ting.,Song, Yuanli.,Wang, Mingyu.,Liu, Liping.,...&Luo, Cheng.(2022).Discovery of Small-Molecule Degraders of the CDK9-Cyclin T1 Complex for Targeting Transcriptional Addiction in Prostate Cancer.JOURNAL OF MEDICINAL CHEMISTRY.
MLA	Li, Jiacheng,et al."Discovery of Small-Molecule Degraders of the CDK9-Cyclin T1 Complex for Targeting Transcriptional Addiction in Prostate Cancer".JOURNAL OF MEDICINAL CHEMISTRY (2022).