Y06014 is a selective BET inhibitor for the treatment of prostate cancer.

Abstract

Bromodomain and extra-terminal proteins (BETs) are potential targets for the therapeutic treatment of prostate cancer (PC). Herein, we report the design, the synthesis, and a structure-activity relationship study of 6-(3,5-dimethylisoxazol-4-yl)benzo[cd]indol-2(1H)-one derivative as novel selective BET inhibitors. One representative compound, 19 (Y06014), bound to BRD4(1) in the low micromolar range and demonstrated high selectivity for BRD4(1) over other non-BET bromodomain-containing proteins. This molecule also potently inhibited cell growth, colony formation, and mRNA expression of AR-regulated genes in PC cell lines. Y06014 also shows stronger activity than the second-generation antiandrogen enzalutamide. Y06014 may serve as a new small molecule probe for further validation of BET as a molecular target for PC drug development.

• Authors: Tian-Bang Wu, Qiu-Ping Xiang, Chao Wang, Chun Wu, Cheng Zhang, Mao-Feng Zhang, Zhao-Xuan Liu, Yan Zhang, Lin-Jiu Xiao, Yong Xu
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 42 Issue 12 Pg. 2120-2131 (Dec 2021) ISSN: 1745-7254 [Electronic] United States
• PMID: 33654218 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to CPS and SIMM.

Chemical References

• Antineoplastic Agents
• BRD4 protein, human
• Cell Cycle Proteins
• Indoles
• Isoxazoles
• Small Molecule Libraries
• Transcription Factors

Topics

• Antineoplastic Agents (chemical synthesis, metabolism, pharmacology)
• Cell Cycle Proteins (chemistry, metabolism)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Indoles (chemical synthesis, metabolism, pharmacology)
• Isoxazoles (chemical synthesis, metabolism, pharmacology)
• Male
• Molecular Docking Simulation
• Molecular Structure
• Prostatic Neoplasms (drug therapy)
• Protein Binding
• Protein Domains
• Small Molecule Libraries (chemical synthesis, metabolism, pharmacology)
• Structure-Activity Relationship
• Transcription Factors (chemistry, metabolism)