CDK2 的抑制剂和 PROTACs:挑战与机遇。

IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Expert Opinion on Drug Discovery Pub Date : 2024-09-01 Epub Date: 2024-07-12 DOI:10.1080/17460441.2024.2376655
Yangjie Zeng, Xiaodong Ren, Pengyao Jin, Zhida Fan, Mengguang Liu, Yali Zhang, Linzhao Li, Ming Zhuo, Jubo Wang, Zhiyu Li, Min Wu
{"title":"CDK2 的抑制剂和 PROTACs:挑战与机遇。","authors":"Yangjie Zeng, Xiaodong Ren, Pengyao Jin, Zhida Fan, Mengguang Liu, Yali Zhang, Linzhao Li, Ming Zhuo, Jubo Wang, Zhiyu Li, Min Wu","doi":"10.1080/17460441.2024.2376655","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Abundant evidence suggests that the overexpression of CDK2-cyclin A/E complex disrupts normal cell cycle regulation, leading to uncontrolled proliferation of cancer cells. Thus, CDK2 has become a promising therapeutic target for cancer treatment. In recent years, insights into the structures of the CDK2 catalytic site and allosteric pockets have provided notable opportunities for developing more effective clinical candidates of CDK2 inhibitors.</p><p><strong>Area covered: </strong>This article reviews the latest CDK2 inhibitors that have entered clinical trials and discusses the design and discovery of the most promising new preclinical CDK2 inhibitors in recent years. Additionally, it summarizes the development of allosteric CDK2 inhibitors and CDK2-targeting PROTACs. The review encompasses strategies for inhibitor and PROTAC design, structure-activity relationships, as well as in vitro and in vivo biological assessments.</p><p><strong>Expert opinion: </strong>Despite considerable effort, no CDK2 inhibitor has yet received FDA approval for marketing due to poor selectivity and observed toxicity in clinical settings. Future research must prioritize the optimization of the selectivity, potency, and pharmacokinetics of CDK2 inhibitors and PROTACs. Moreover, exploring combination therapies incorporating CDK2 inhibitors with other targeted agents, or the design of multi-target inhibitors, presents significant promise for advancing cancer treatment strategies.</p>","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":null,"pages":null},"PeriodicalIF":6.0000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Inhibitors and PROTACs of CDK2: challenges and opportunities.\",\"authors\":\"Yangjie Zeng, Xiaodong Ren, Pengyao Jin, Zhida Fan, Mengguang Liu, Yali Zhang, Linzhao Li, Ming Zhuo, Jubo Wang, Zhiyu Li, Min Wu\",\"doi\":\"10.1080/17460441.2024.2376655\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Abundant evidence suggests that the overexpression of CDK2-cyclin A/E complex disrupts normal cell cycle regulation, leading to uncontrolled proliferation of cancer cells. Thus, CDK2 has become a promising therapeutic target for cancer treatment. In recent years, insights into the structures of the CDK2 catalytic site and allosteric pockets have provided notable opportunities for developing more effective clinical candidates of CDK2 inhibitors.</p><p><strong>Area covered: </strong>This article reviews the latest CDK2 inhibitors that have entered clinical trials and discusses the design and discovery of the most promising new preclinical CDK2 inhibitors in recent years. Additionally, it summarizes the development of allosteric CDK2 inhibitors and CDK2-targeting PROTACs. The review encompasses strategies for inhibitor and PROTAC design, structure-activity relationships, as well as in vitro and in vivo biological assessments.</p><p><strong>Expert opinion: </strong>Despite considerable effort, no CDK2 inhibitor has yet received FDA approval for marketing due to poor selectivity and observed toxicity in clinical settings. Future research must prioritize the optimization of the selectivity, potency, and pharmacokinetics of CDK2 inhibitors and PROTACs. Moreover, exploring combination therapies incorporating CDK2 inhibitors with other targeted agents, or the design of multi-target inhibitors, presents significant promise for advancing cancer treatment strategies.</p>\",\"PeriodicalId\":12267,\"journal\":{\"name\":\"Expert Opinion on Drug Discovery\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Expert Opinion on Drug Discovery\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/17460441.2024.2376655\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/12 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Expert Opinion on Drug Discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/17460441.2024.2376655","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/12 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

摘要

导言:大量证据表明,CDK2-细胞周期蛋白 A/E 复合物的过度表达会破坏正常的细胞周期调控,导致癌细胞失控增殖。因此,CDK2 已成为一种很有前景的癌症治疗靶点。近年来,对 CDK2 催化位点和异位口袋结构的深入研究为开发更有效的临床候选 CDK2 抑制剂提供了显著的机会:本文回顾了已进入临床试验的最新 CDK2 抑制剂,并讨论了近年来最有前景的新型临床前 CDK2 抑制剂的设计和发现。此外,文章还总结了异位CDK2抑制剂和CDK2靶向PROTACs的开发情况。综述包括抑制剂和 PROTAC 的设计策略、结构-活性关系以及体外和体内生物学评估:尽管做了大量努力,但由于选择性差和临床观察到的毒性,CDK2 抑制剂尚未获得 FDA 批准上市。未来的研究必须优先优化 CDK2 抑制剂和 PROTACs 的选择性、药效和药代动力学。此外,探索将 CDK2 抑制剂与其他靶向药物相结合的联合疗法,或设计多靶点抑制剂,为推进癌症治疗策略带来了巨大希望。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibitors and PROTACs of CDK2: challenges and opportunities.

Introduction: Abundant evidence suggests that the overexpression of CDK2-cyclin A/E complex disrupts normal cell cycle regulation, leading to uncontrolled proliferation of cancer cells. Thus, CDK2 has become a promising therapeutic target for cancer treatment. In recent years, insights into the structures of the CDK2 catalytic site and allosteric pockets have provided notable opportunities for developing more effective clinical candidates of CDK2 inhibitors.

Area covered: This article reviews the latest CDK2 inhibitors that have entered clinical trials and discusses the design and discovery of the most promising new preclinical CDK2 inhibitors in recent years. Additionally, it summarizes the development of allosteric CDK2 inhibitors and CDK2-targeting PROTACs. The review encompasses strategies for inhibitor and PROTAC design, structure-activity relationships, as well as in vitro and in vivo biological assessments.

Expert opinion: Despite considerable effort, no CDK2 inhibitor has yet received FDA approval for marketing due to poor selectivity and observed toxicity in clinical settings. Future research must prioritize the optimization of the selectivity, potency, and pharmacokinetics of CDK2 inhibitors and PROTACs. Moreover, exploring combination therapies incorporating CDK2 inhibitors with other targeted agents, or the design of multi-target inhibitors, presents significant promise for advancing cancer treatment strategies.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
10.20
自引率
1.60%
发文量
78
审稿时长
6-12 weeks
期刊介绍: Expert Opinion on Drug Discovery (ISSN 1746-0441 [print], 1746-045X [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles on novel technologies involved in the drug discovery process, leading to new leads and reduced attrition rates. Each article is structured to incorporate the author’s own expert opinion on the scope for future development. The Editors welcome: Reviews covering chemoinformatics; bioinformatics; assay development; novel screening technologies; in vitro/in vivo models; structure-based drug design; systems biology Drug Case Histories examining the steps involved in the preclinical and clinical development of a particular drug The audience consists of scientists and managers in the healthcare and pharmaceutical industry, academic pharmaceutical scientists and other closely related professionals looking to enhance the success of their drug candidates through optimisation at the preclinical level.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信