2. Academic Validation
  3. Design, synthesis and biological evaluation of a novel spiro oxazolidinedione as potent p300/CBP HAT inhibitor for the treatment of ovarian cancer

Design, synthesis and biological evaluation of a novel spiro oxazolidinedione as potent p300/CBP HAT inhibitor for the treatment of ovarian cancer

  • Bioorg Med Chem. 2021 Dec 15;52:116512. doi: 10.1016/j.bmc.2021.116512.
Hong Ding 1,  Yuan Pei 2,  Yuanqing Li 2,  Wen Xu 3,  Lianghe Mei 4,  Zeng Hou 5,  Yiman Guang 2,  Liyuan Cao 6,  Peizhuo Li 4,  Haijing Cao 7,  Jinlei Bian 8,  Kaixian Chen 9,  Cheng Luo 5,  Bing Zhou 5,  Ting Zhang 10,  Zhiyu Li 11,  Yaxi Yang 12
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
  • 3 Hospital & Institute of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023,China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 7 Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China.
  • 8 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 9 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023,China.
  • 10 Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China. Electronic address: zhangting@sippr.org.cn.
  • 11 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: zhiyuli@cpu.edu.cn.
  • 12 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China. Electronic address: yangyaxi@simm.ac.cn.
PMID: 34801827 DOI: 10.1016/j.bmc.2021.116512
Abstract

Histone acetylation is one of the most essential parts of epigenetic modification, mediating a variety of complex biological functions. In these procedure, p300/CBP could catalyze the acetylation of lysine 27 on histone 3 (H3K27ac), and had been reported to mediate tumorigenesis and development in a variety of tumors by enhancing chromatin transcription activity. Ovarian Cancer, as an extremely malignant tumor, has also been observed to undergo abnormal acetylation of histones. However, whether the treatment of ovarian Cancer could be achieved by inhibiting the acetylation activity of p300/CBP on H3K27 has not been well investigated. In this article, we modified the structure of p300/CBP HAT domain inhibitor A-485 and obtained a highly active small molecule known as 13f, which has an IC50 value of 0.49 nM for inhibiting the in vitro Enzyme activity of p300, as well as the anti-proliferation IC50 value on ovarian Cancer cell line OVCAR-3 was 153 nM. In addition, 13f had strong acetylase family selectivity, good metabolic stability and promising in vivo anti-tumor activity in OVCAR-3 xenograft model. The discovery of 13f revealed a more active chemical entity of the HATs domain of p300/CBP and provided a novel idea for the application of epigenetic inhibitors in the treatment of ovarian Cancer.

Keywords

Epigenetics; Histone acetyltransferase; Ovarian cancer; P300/CBP.

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