利用PROTAC技术推进目标验证。

IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
M Leora Spitz, Aseel Kashkush, Raphael I Benhamou
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引用次数: 0

摘要

靶向蛋白降解(TPD)是一项前沿技术,为药物发现和开发提供了新的途径。靶向嵌合体(PROteolysis TArgeting Chimeras, PROTACs)是最成熟和先进的TPD策略,通过利用细胞的天然蛋白质降解机制,能够选择性降解疾病相关和“不可药物”的感兴趣蛋白(POIs)。为了确认protac诱导的接近驱动蛋白质降解,必须彻底评估靶标验证和三元络合物的形成。涵盖领域:从这个角度来看,作者详细介绍了一些最广泛使用的硅、结构、体外和celllo方法,以验证PROTAC目标接合和三元络合物形成。此外,他们还讨论了PROTACs作为新靶标鉴定和验证的化学探针的日益增长的使用。专家意见:在PROTAC方法中,靶标验证是必不可少的,正在进行的PROTAC研究应优先使用在生理相关细胞条件下进行的测定来确认三元复合物的形成。作者认为,蛋白质组学分析是阐明PROTACs的机制、选择性和结果的最有价值的工具之一。他们还对PROTACs在药物开发中的未来以及它们作为确认靶标作用的探针的使用持乐观态度。虽然PROTAC技术正在迅速发展,但它仍然拥有未来探索的巨大机会,为进一步的化学和生物研究以及推动新药开发提供了巨大的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Advancing target validation with PROTAC technology.

Introduction: Targeted protein degradation (TPD) is a cutting-edge technology that provides new avenues for drug discovery and development. PROteolysis TArgeting Chimeras (PROTACs) are the most established and advanced TPD strategy, enabling the selective degradation of disease-associated and 'undruggable' proteins of interest (POIs) by leveraging the cell's natural protein degradation machinery. To confirm that PROTAC-induced proximity drives protein degradation, target validation and ternary complex formation must be thoroughly assessed.

Areas covered: In this perspective, the authors detail some of the most widely used in silico, structural, in vitro, and in cellulo methods to validate PROTAC target engagement and ternary complex formation. Additionally, they discuss the growing use of PROTACs as chemical probes for novel target identification and validation.

Expert opinion: Target validation is essential in the PROTAC approach, and ongoing PROTAC studies should prioritize confirming ternary complex formation using assays conducted under physiologically relevant cellular conditions. The authors believe that proteomics analyses are among the most valuable tools for elucidating the mechanism, selectivity, and outcomes of PROTACs. They also remain optimistic about the future of PROTACs in drug development and their use as probes to confirm target engagement. While PROTAC technology is rapidly advancing, it still holds vast opportunities for future exploration, offering significant potential to further both chemical and biological research and to drive the development of new drugs.

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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.
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