Discovery of Small-Molecule Degraders of the CDK9-Cyclin T1 Complex for Targeting Transcriptional Addiction in Prostate Cancer
文献类型：期刊论文
| 作者 | Li, Jiacheng1,3; Liu, Ting2; Song, Yuanli2,3,4,5; Wang, Mingyu1,3; Liu, Liping1,3; Zhu, Hongwen3,4,5; Li, Qi1,3; Lin, Jin2; Jiang, Hualiang1,3 ; Chen, Kaixian1,3
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2022-08-25 |
| 卷号 | 65期号:16页码:11034-11057 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.2c00257 |
| 文献子类 | Article |
| 英文摘要 | 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). |
| WOS关键词 | CELL-CYCLE ; MEDIATED DEGRADATION ; KINASE ; INHIBITION ; EXPRESSION ; RESISTANCE |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000838291400001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309313]  |
| 专题 | 新药研究国家重点实验室 |
| 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 |
| 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,2022,65(16):11034-11057. |
| 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,65(16),11034-11057. |
| 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 65.16(2022):11034-11057. |
入库方式： OAI收割
来源：上海药物研究所
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