2. Academic Validation
  3. Discovery, optimization and evaluation of 1-(indolin-1-yl)ethan-1-ones as novel selective TRIM24/BRPF1 bromodomain inhibitors

Discovery, optimization and evaluation of 1-(indolin-1-yl)ethan-1-ones as novel selective TRIM24/BRPF1 bromodomain inhibitors

  • Eur J Med Chem. 2022 Jun 5;236:114311. doi: 10.1016/j.ejmech.2022.114311.
Qiuping Xiang 1,  Guolong Luo 2,  Cheng Zhang 3,  Qingqing Hu 2,  Chao Wang 2,  Tianbang Wu 4,  Hongrui Xu 5,  Jiankang Hu 2,  Xiaoxi Zhuang 3,  Maofeng Zhang 6,  Shuang Wu 3,  Jinxin Xu 7,  Yan Zhang 3,  Jinsong Liu 7,  Yong Xu 8
Affiliations

Affiliations

  • 1 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. Electronic address: xiang_qiuping@gibh.ac.cn.
  • 2 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.
  • 3 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.
  • 4 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; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 5 GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
  • 6 College of Pharmacy, Taizhou Polytechnic College, Taizhou, 225300, China.
  • 7 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
  • 8 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; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, 510530, China. Electronic address: xu_yong@gibh.ac.cn.
PMID: 35385803 DOI: 10.1016/j.ejmech.2022.114311
Abstract

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.

Keywords

BRPF1; Bromodomain; Dual targeting inhibitor; Structure-guided design; TRIM24.

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