{"title":"Pt(IV)-PROTAC Complexes with Synergistic Antitumor Activity and Enhanced Membrane Permeability","authors":"Cheng-xin Li, Zhi-ru Zou, Shan Xu, Jia-hui Shi, Yong Zou, Ming Yan, Xue-jing Zhang","doi":"10.1021/acs.jmedchem.4c02909","DOIUrl":null,"url":null,"abstract":"A class of Pt(IV)-PROTAC complexes was designed and synthesized with dual aims of inducing DNA strand damage and inhibiting DNA repair. These complexes showed good antiproliferative activity against a range of cancer cell lines. Enhanced intracellular uptake of platinum and PROTAC was observed. Multiple mechanisms of action were identified, including the induction of DNA damage, disruption of DNA repair, and activation of mitochondrial-dependent apoptosis. One of the Pt(IV)-PROTACs, <b>CW-2</b>, showed excellent antitumor activity in a xenograft mouse model. These results suggest that Pt(IV)-PROTAC represents a promising strategy for the development of novel antitumor therapeutics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"81 1","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-04-04","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.4c02909","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
A class of Pt(IV)-PROTAC complexes was designed and synthesized with dual aims of inducing DNA strand damage and inhibiting DNA repair. These complexes showed good antiproliferative activity against a range of cancer cell lines. Enhanced intracellular uptake of platinum and PROTAC was observed. Multiple mechanisms of action were identified, including the induction of DNA damage, disruption of DNA repair, and activation of mitochondrial-dependent apoptosis. One of the Pt(IV)-PROTACs, CW-2, showed excellent antitumor activity in a xenograft mouse model. These results suggest that Pt(IV)-PROTAC represents a promising strategy for the development of novel antitumor therapeutics.
我们设计并合成了一类铂（IV）-PROTAC 复合物，具有诱导 DNA 链损伤和抑制 DNA 修复的双重目的。这些复合物对一系列癌细胞株显示出良好的抗增殖活性。观察到铂和 PROTAC 在细胞内的吸收增强。研究发现了多种作用机制，包括诱导 DNA 损伤、破坏 DNA 修复和激活线粒体依赖性凋亡。其中一种铂(IV)-PROTAC--CW-2，在异种移植小鼠模型中显示出卓越的抗肿瘤活性。这些结果表明，Pt(IV)-PROTAC 是开发新型抗肿瘤疗法的一种有前途的策略。
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.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
