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

Hong Ding; Yuan Pei; Yuanqing Li; Wen Xu; Lianghe Mei; Zeng Hou; Yiman Guang; Liyuan Cao; Peizhuo Li; Haijing Cao; Jinlei Bian; Kaixian Chen; Cheng Luo; Bing Zhou; Ting Zhang; Zhiyu Li; Yaxi Yang

doi:10.1016/j.bmc.2021.116512

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. Epub 2021 Nov 10.

Authors

Hong Ding¹, Yuan Pei², Yuanqing Li², Wen Xu³, Lianghe Mei⁴, Zeng Hou⁵, Yiman Guang², Liyuan Cao⁶, Peizhuo Li⁴, Haijing Cao⁷, Jinlei Bian⁸, Kaixian Chen⁹, Cheng Luo⁵, Bing Zhou⁵, Ting Zhang¹⁰, Zhiyu Li¹¹, Yaxi Yang¹²

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Female
Humans
Molecular Structure
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology
Oxazoles / chemical synthesis
Oxazoles / chemistry
Oxazoles / pharmacology*
Spiro Compounds / chemical synthesis
Spiro Compounds / chemistry
Spiro Compounds / pharmacology*
Structure-Activity Relationship
p300-CBP Transcription Factors / antagonists & inhibitors*
p300-CBP Transcription Factors / metabolism

Substances

Antineoplastic Agents
Enzyme Inhibitors
Oxazoles
Spiro Compounds
p300-CBP Transcription Factors