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

• Published in: Bioorganic & medicinal chemistry Vol. 52; p. 116512
• Main Authors: Ding, Hong, Pei, Yuan, Li, Yuanqing, Xu, Wen, Mei, Lianghe, Hou, Zeng, Guang, Yiman, Cao, Liyuan, Li, Peizhuo, Cao, Haijing, Bian, Jinlei, Chen, Kaixian, Luo, Cheng, Zhou, Bing, Zhang, Ting, Li, Zhiyu, Yang, Yaxi
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2021; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemistry & Molecular Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Epigenetics; Female; Histone acetyltransferase; Humans; Life Sciences & Biomedicine; Molecular Structure; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Oxazoles - chemical synthesis; Oxazoles - chemistry; Oxazoles - pharmacology; p300-CBP Transcription Factors - antagonists & inhibitors; p300-CBP Transcription Factors - metabolism; P300/CBP; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure-Activity Relationship; Epigenetics; P300/CBP; Histone acetyltransferase; Ovarian cancer; LANGUAGE; PROTEIN; THERAPY; CHROMATIN; ACETYLATION; ENHANCERS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2021.116512

[Display omitted] 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.