ATM, ATR和DNA-PK抑制剂作为前瞻性癌症治疗药物的药物化学突破。

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ram Sharma, Anshul Mishra, Monika Bhardwaj, Gurpreet Singh, Larasati Vanya Indira Harahap, Sakshi Vanjani, Chun Hsu Pan, Kunal Nepali
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引用次数: 0

摘要

本文综述了共济失调毛细血管扩张突变激酶(ATM)、ATM和rad3相关激酶(ATR)以及DNA依赖性蛋白激酶(DNA- pk)在DNA损伤反应(DDR)中的重要作用及其在癌症中的意义。重点放在这些激酶之间复杂的相互作用上,强调它们在维持基因组完整性和促进失调条件下肿瘤发展方面的协作和独特作用。此外,该综述还涵盖了正在进行的ATM/ATR/DNA-PK抑制剂作为抗肿瘤药物的临床试验、专利文献和药物化学活动。值得注意的是,药物化学运动采用了稳健的药物设计策略,旨在组装具有放大DDR激酶抑制能力的新结构模板,以及战胜现有DDR激酶抑制剂的药代动力学缺陷。鉴于通过这些努力取得的成功,DNA修复激酶抑制剂的临床管道预计将很快得到合理数量的可处理条目(DDR激酶抑制剂)的补充。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Medicinal chemistry breakthroughs on ATM, ATR, and DNA-PK inhibitors as prospective cancer therapeutics.

This review discusses the critical roles of Ataxia Telangiectasia Mutated Kinase (ATM), ATM and Rad3-related Kinase (ATR), and DNA-dependent protein kinase (DNA-PK) in the DNA damage response (DDR) and their implications in cancer. Emphasis is placed on the intricate interplay between these kinases, highlighting their collaborative and distinct roles in maintaining genomic integrity and promoting tumour development under dysregulated conditions. Furthermore, the review covers ongoing clinical trials, patent literature, and medicinal chemistry campaigns on ATM/ATR/DNA-PK inhibitors as antitumor agents. Notably, the medicinal chemistry campaigns employed robust drug design strategies and aimed at assembling new structural templates with amplified DDR kinase inhibitory ability, as well as outwitting the pharmacokinetic liabilities of the existing DDR kinase inhibitors. Given the success attained through such endeavours, the clinical pipeline of DNA repair kinase inhibitors is anticipated to be supplemented by a reasonable number of tractable entries (DDR kinase inhibitors) soon.

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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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