溴尿嘧啶
化学
表观遗传学
癌症研究
药理学
计算生物学
生物化学
生物
基因
作者
Qiuping Xiang,Guolong Luo,Cheng Zhang,Qingqing Hu,Chao Wang,Tianbang Wu,H. Eric Xu,Jiankang Hu,Xiaoxi Zhuang,Mao-feng Zhang,Shuang Wu,Jinxin Xu,Yan Zhang,Jinsong Liu,Yong Xu
标识
DOI:10.1016/j.ejmech.2022.114311
摘要
TRIM24 (tripartite motif-containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are epigenetics "readers" and potential therapeutic targets for cancer and other diseases. Here we describe the structure-guided design of 1-(indolin-1-yl)ethan-1-ones as novel TRIM24/BRPF1 bromodomain inhibitors. The representative compound 20l (Y08624) is a new TRIM24/BRPF1 dual inhibitor, with IC50 values of 0.98 and 1.16 μM, respectively. Cellular activity of 20l was validated by viability assay in prostate cancer (PC) cell lines. In PC xenograft models, 20l suppressed tumor growth (50 mg/kg/day, TGI = 53%) without exhibiting noticeable toxicity. Compound 20l represents a versatile starting point for the development of more potent TRIM24/BRPF1 inhibitors.
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