新型选择性TRIM24/BRPF1溴结构域抑制剂1-(吲哚啉-1-基)乙-1-酮的发现、优化及评估
Discovery, optimization and evaluation of 1-(indolin-1-yl)ethan-1-ones as novel selective TRIM24/BRPF1 bromodomain inhibitors.
作者信息
Xiang Qiuping, Luo Guolong, Zhang Cheng, Hu Qingqing, Wang Chao, Wu Tianbang, Xu Hongrui, Hu Jiankang, Zhuang Xiaoxi, Zhang Maofeng, Wu Shuang, Xu Jinxin, Zhang Yan, Liu Jinsong, Xu Yong
机构信息
Guangdong Provincial Key Laboratory of Biocomputing, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China.
Guangdong Provincial Key Laboratory of Biocomputing, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China; University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing, 100049, China.
出版信息
Eur J Med Chem. 2022 Jun 5;236:114311. doi: 10.1016/j.ejmech.2022.114311. Epub 2022 Mar 28.
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 IC 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.
TRIM24（含三联基序蛋白24）和BRPF1（含溴结构域和PHD指蛋白1）是表观遗传学的“读取器”，也是癌症和其他疾病潜在的治疗靶点。在此，我们描述了作为新型TRIM24/BRPF1溴结构域抑制剂的1-（吲哚啉-1-基）乙-1-酮的结构导向设计。代表性化合物20l（Y08624）是一种新型TRIM24/BRPF1双重抑制剂，其IC值分别为0.98和1.16μM。通过前列腺癌（PC）细胞系的活力测定验证了20l的细胞活性。在PC异种移植模型中，20l抑制肿瘤生长（50mg/kg/天，TGI = 53%），且未表现出明显毒性。化合物20l是开发更有效TRIM24/BRPF1抑制剂的通用起点。
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