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Discovery of a Potent, selective and orally bioavailable CDK9 degrader for targeting transcription regulation in Triple-Negative breast cancer

文献类型：期刊论文

作者Nie, Hui-Jun4,5; Li, Ben-Fu1,4; Sun, Jingya3; Yuan, Yali2; Zhang, Zhi-Gao1,5; Hu, Hao4; Wang, Wen-Jing1,5; Chen, Ziqiang1,3; Wang, Simei1,3; Huang, Wensi2
刊名BIOORGANIC CHEMISTRY
出版日期2024-12-01
卷号153页码:16
关键词Triple-negative breast cancer Targeting transcription regulation Orally bioavailable degrader PROTAC Cyclin-dependent Kinase 9
ISSN号0045-2068
DOI10.1016/j.bioorg.2024.107876
通讯作者Yu, Jinghua(yujinghua2@simm.ac.cn) ; Huang, Ruimin(rmhuang@simm.ac.cn) ; Chen, Xiao-Hua(xhchen@simm.ac.cn)
英文摘要Triple-negative breast cancer (TNBC) is a highly aggressive, heterogeneous and invasive subtype of breast cancer with very limited effective modalities of treatment. Degrading the critical transcription regulator cyclindependent kinase 9 (CDK9) by proteolysis targeting chimeras (PROTACs) has shown promising potential for treating TNBC. However, to date, CDK9-targeting PROTACs for oral administration in treatment of cancers have not been reported. We herein present the design, synthesis, and extensive biological evaluation of a series of novel PROTACs as orally bioavailable, potent and selective degraders of CDK9 for targeting transcription regulation in triple-negative breast cancer. The developed compound 29 exhibited a desired potency (DC50 = 3.94 nM) with high efficacy (Dmax = 96 %) on CDK9 degradation, and effectively inhibited the proliferation of TNBC MDA-MB-231 cells. Mechanistic investigations revealed that compound 29 is a bona fide CDK9 degrader and can substantially downregulate the downstream targets c-Myc and MCL-1. Furthermore, compound 29 displayed favorable oral bioavailability in mice, and oral administration of degrader 29 significantly depleted CDK9 protein in TNBC tumor tissues and exhibited tumor growth inhibition in TNBC xenograft mice models. Collectively, our work established that degrader 29 is a highly potent and selective degraders of CDK9 with satisfactory oral bioavailability, which holds promising potential for the treatment of TNBC.
WOS关键词PROTACS
资助项目National Science Foundation of China (NSFC)[22177120] ; National Science Foundation of China (NSFC)[82172001] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0220233001] ; Shanghai Municipal Science and Technology Major Project
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:001335738800001
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/313960]  
专题新药研究国家重点实验室
通讯作者Yu, Jinghua; Huang, Ruimin; Chen, Xiao-Hua
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China
推荐引用方式
GB/T 7714		 Nie, Hui-Jun,Li, Ben-Fu,Sun, Jingya,et al. Discovery of a Potent, selective and orally bioavailable CDK9 degrader for targeting transcription regulation in Triple-Negative breast cancer[J]. BIOORGANIC CHEMISTRY,2024,153:16.
APA Nie, Hui-Jun.,Li, Ben-Fu.,Sun, Jingya.,Yuan, Yali.,Zhang, Zhi-Gao.,...&Chen, Xiao-Hua.(2024).Discovery of a Potent, selective and orally bioavailable CDK9 degrader for targeting transcription regulation in Triple-Negative breast cancer.BIOORGANIC CHEMISTRY,153,16.
MLA Nie, Hui-Jun,et al."Discovery of a Potent, selective and orally bioavailable CDK9 degrader for targeting transcription regulation in Triple-Negative breast cancer".BIOORGANIC CHEMISTRY 153(2024):16.

入库方式： OAI收割

来源：上海药物研究所

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