Xueqian Yang , Xiangnan Zheng , Cheng Liu , Jiaqing Zheng , Xu Dong , Wengang Ren , Tao Zhang , Hongxiang Lou , Peihong Fan
{"title":"Design, synthesis, and biological evaluation of novel PROTACs compounds with good ERα degradation ability","authors":"Xueqian Yang , Xiangnan Zheng , Cheng Liu , Jiaqing Zheng , Xu Dong , Wengang Ren , Tao Zhang , Hongxiang Lou , Peihong Fan","doi":"10.1016/j.bmc.2025.118111","DOIUrl":null,"url":null,"abstract":"<div><div>A series of ER-PROTACs compounds were designed, synthesized and tested for their ability to degrade estrogen receptor proteins and exhibit Human breast cancer cells (MCF-7) inhibition activity. Molecular docking simulations were performed using Discovery studio. Among these compounds, <strong>QDE-003-W</strong> had the highest estrogen receptor protein degradation ability and cellular activity, with a DC<sub>50</sub> value of 95 nM, for estrogen receptor protein degradation and an IC<sub>50</sub> value of 30.2 nM for cellular activity. Furthermore, the molecular docking study revealed that the biological activity of <strong>QDE-003-W</strong> depended on its suitable linker length, which gave us some reference significance for the study of ER-PROTACs. And compared with fulvestrant, <strong>QDE-003-W</strong> exhibited more favorable pharmacokinetic (PK) characteristics. No significant adverse side effects were observed under the administration protocol, which indicates that the tested mice had excellent tolerance to both the administration method and the dosage. Such favorable PK characteristics and safety features further enhance the prospects of QDE-003-W as a viable candidate for subsequent preclinical and clinical development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118111"},"PeriodicalIF":3.3000,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0968089625000525","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
A series of ER-PROTACs compounds were designed, synthesized and tested for their ability to degrade estrogen receptor proteins and exhibit Human breast cancer cells (MCF-7) inhibition activity. Molecular docking simulations were performed using Discovery studio. Among these compounds, QDE-003-W had the highest estrogen receptor protein degradation ability and cellular activity, with a DC50 value of 95 nM, for estrogen receptor protein degradation and an IC50 value of 30.2 nM for cellular activity. Furthermore, the molecular docking study revealed that the biological activity of QDE-003-W depended on its suitable linker length, which gave us some reference significance for the study of ER-PROTACs. And compared with fulvestrant, QDE-003-W exhibited more favorable pharmacokinetic (PK) characteristics. No significant adverse side effects were observed under the administration protocol, which indicates that the tested mice had excellent tolerance to both the administration method and the dosage. Such favorable PK characteristics and safety features further enhance the prospects of QDE-003-W as a viable candidate for subsequent preclinical and clinical development.
期刊介绍:
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.