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Design of Selective BRD4 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease

文献类型：期刊论文

作者Yang, Yueyue3,4; Liu, Hongli2; Yuan, Haoxing1,2; Lyu, Kaikai3,4; Zhong, Haiyang2; Li, Yanlian4; Cao, Danyan4; Zhao, Wenchao2; Zhang, Haoran2; Xiong, Bing2,3,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-02-13
页码18
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c02128
通讯作者Xiong, Bing(bxiong@simm.ac.cn) ; Chen, Danqi(dqchen@simm.ac.cn) ; Guo, Dong(guo@xzhmu.edu.cn)
英文摘要Epigenetic modulation plays a pivotal role in restraining tumor progression by governing gene expression and protein function. Autosomal dominant polycystic kidney disease (ADPKD), characterized by neoplastic-like progression, can be managed by inhibiting cyst expansion. Of note, the epigenetic regulator BRD4 has been implicated in ADPKD's development. Our prior research unveiled a class of (pyrazol-3-yl) pyrimidin-4-amine compounds as potent BRD4 inhibitors with additional kinase inhibition, which might induce unwanted biological activities. To address this, this study focused on creating selective BRD4 inhibitors through structure-guided design, minimizing off-target kinase interactions. Specifically, compound 23 emerged as an efficacious and selective BRD4 inhibitor in cellular and embryonic kidney models of ADPKD, along with encouraging outcomes in murine models. Collectively, these results highlight the therapeutic potential of targeted BRD4 inhibition as a safe and efficacious strategy for managing ADPKD.
资助项目National Natural Science Foundation of China[22377103] ; National Natural Science Foundation of China[82173658] ; National Natural Science Foundation of China[22077110] ; National Natural Science Foundation of China[BK20240051] ; Jiangsu Outstanding Youth Fund
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001420607300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/316227]  
专题中国科学院上海药物研究所
通讯作者Xiong, Bing; Chen, Danqi; Guo, Dong
作者单位1.Southern Med Univ, Sch Pharmaceut Sci, Guangdong Prov Key Lab New Drug Screening, NMPA Key Lab Drug Metab Res & Evaluat, Guangzhou 510515, Peoples R China
2.Xuzhou Med Univ, Jiangsu Key Lab New Drug Res & Clin Pharm, Xuzhou 221004, Jiangsu, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Yueyue,Liu, Hongli,Yuan, Haoxing,et al. Design of Selective BRD4 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025:18.
APA Yang, Yueyue.,Liu, Hongli.,Yuan, Haoxing.,Lyu, Kaikai.,Zhong, Haiyang.,...&Guo, Dong.(2025).Design of Selective BRD4 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease.JOURNAL OF MEDICINAL CHEMISTRY,18.
MLA Yang, Yueyue,et al."Design of Selective BRD4 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease".JOURNAL OF MEDICINAL CHEMISTRY (2025):18.

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来源：上海药物研究所

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