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Discovery of Orally Bioavailable and Potent CDK9 Inhibitors for Targeting Transcription Regulation in Triple-Negative Breast Cancer

文献类型：期刊论文

作者Wang, Wen-Jing7,10; Gao, Lixin6,9; Wang, Simei7,8; Huang, Wensi7,8; Meng, Xin-Yu7,10; Hu, Hao10; Chen, Ziqiang7,8; Sun, Jingya8; Yuan, Yali5; Zhou, Yubo4,7,9
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-06-17
卷号67期号:12页码:10035-10056
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00233
通讯作者Diao, Xingxing(xxdiao@simm.ac.cn) ; 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) represents a highly aggressive and heterogeneous malignancy. Currently, effective therapies for TNBC are very limited and remain a significant unmet clinical need. Targeting the transcription-regulating cyclin-dependent kinase 9 (CDK9) has emerged as a promising avenue for therapeutic treatment of TNBC. Herein, we report the design, synthesis, optimization, and evaluation of a new series of aminopyrazolotriazine compounds as orally bioavailable, potent, and CDK9/2 selectivity-improved inhibitors, enabling efficacious inhibition of TNBC cell growth, as well as notable antitumor effect in TNBC models. The compound C35 demonstrated low-nanomolar potency with substantially improved CDK9/2 selectivity, downregulated the CDK9-downstream targets (e.g., MCL-1), and induced apoptosis in TNBC cell lines. Moreover, with the desired oral bioavailability, oral administration of C35 could significantly suppress the tumor progression in two TNBC mouse models. This study demonstrates that target transcriptional regulation is an effective strategy and holds promising potential as a targeted therapy for the treatment of TNBC.
WOS关键词CYCLIN-DEPENDENT KINASES ; IN-VITRO ; VIVO ; ADDICTION ; CELLS ; MYC
资助项目National Natural Science Foundation of China[82172001] ; National Science Foundation of China (NSFC)[21S11900700] ; Science and Technology Commission of Shanghai Municipality, China ; Shanghai Municipal Science and Technology Major Project[SIMM0220233001] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001250956400001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/311902]  
专题新药研究国家重点实验室
通讯作者Diao, Xingxing; Huang, Ruimin; Li, Jia; Chen, Xiao-Hua
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Inst Drug Discovery & Dev, Zhongshan 528400, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
6.Jiangnan Univ, Sch Life Sci & Hlth Engn, Wuxi 214122, Peoples R China
7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
9.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
10.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Wen-Jing,Gao, Lixin,Wang, Simei,et al. Discovery of Orally Bioavailable and Potent CDK9 Inhibitors for Targeting Transcription Regulation in Triple-Negative Breast Cancer[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(12):10035-10056.
APA Wang, Wen-Jing.,Gao, Lixin.,Wang, Simei.,Huang, Wensi.,Meng, Xin-Yu.,...&Chen, Xiao-Hua.(2024).Discovery of Orally Bioavailable and Potent CDK9 Inhibitors for Targeting Transcription Regulation in Triple-Negative Breast Cancer.JOURNAL OF MEDICINAL CHEMISTRY,67(12),10035-10056.
MLA Wang, Wen-Jing,et al."Discovery of Orally Bioavailable and Potent CDK9 Inhibitors for Targeting Transcription Regulation in Triple-Negative Breast Cancer".JOURNAL OF MEDICINAL CHEMISTRY 67.12(2024):10035-10056.

入库方式： OAI收割

来源：上海药物研究所

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