Jianing Liao, Chenxian Hu, Weitao Fu, Jinbiao Liao, Xin Chai, Luhu Shan, Xiaohong Xu, Tingjun Hou, Rong Sheng, Dan Li
{"title":"Discovery of Thiadiazoleamide Derivatives as Potent, Selective, and Orally Available Antagonists Disrupting Androgen Receptor Homodimer","authors":"Jianing Liao, Chenxian Hu, Weitao Fu, Jinbiao Liao, Xin Chai, Luhu Shan, Xiaohong Xu, Tingjun Hou, Rong Sheng, Dan Li","doi":"10.1021/acs.jmedchem.4c01464","DOIUrl":null,"url":null,"abstract":"Androgen receptor (AR) is an important therapeutic target for prostate cancer (PCa) treatment, but prolonged use of AR antagonists has led to variant drug-resistant mutations. Since all marketed AR antagonists target the ligand binding pocket (LBP) of AR, to mitigate cross-resistance, a new drug pocket named Dimer Interface Pocket was discovered and a novel AR antagonist <b>M17-B15</b> was identified. <b>M17-B15</b> showed strong <i>in vitro</i> efficacy against PCa but had poor pharmacokinetic properties <i>in vivo</i>. In this study, through rational design and structure–activity relationship exploration, a series of thiadiazoleamide derivatives represented by <b>N29</b> (IC<sub>50</sub> = 0.018 μM) were identified with dominant AR antagonistic activity and remarkable anti-PCa activity <i>in vitro</i>. Furthermore, <b>N29</b> effectively inhibited a series of typical drug-resistant AR mutants. The improved oral bioavailability of <b>N29</b> facilitated its efficacy <i>via</i> oral administration, significantly inhibiting LNCaP xenograft tumor <i>in vivo</i>, presenting a promising therapeutic application for PCa.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c01464","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Androgen receptor (AR) is an important therapeutic target for prostate cancer (PCa) treatment, but prolonged use of AR antagonists has led to variant drug-resistant mutations. Since all marketed AR antagonists target the ligand binding pocket (LBP) of AR, to mitigate cross-resistance, a new drug pocket named Dimer Interface Pocket was discovered and a novel AR antagonist M17-B15 was identified. M17-B15 showed strong in vitro efficacy against PCa but had poor pharmacokinetic properties in vivo. In this study, through rational design and structure–activity relationship exploration, a series of thiadiazoleamide derivatives represented by N29 (IC50 = 0.018 μM) were identified with dominant AR antagonistic activity and remarkable anti-PCa activity in vitro. Furthermore, N29 effectively inhibited a series of typical drug-resistant AR mutants. The improved oral bioavailability of N29 facilitated its efficacy via oral administration, significantly inhibiting LNCaP xenograft tumor in vivo, presenting a promising therapeutic application for PCa.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.