各种激酶的脱靶药理活性:潜在的功能和病理副作用

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY
Jonathon R. Green , Prathap Kumar S. Mahalingaiah , Sujatha M. Gopalakrishnan , Michael J. Liguori , Scott W. Mittelstadt , Eric A.G. Blomme , Terry R. Van Vleet
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引用次数: 1

摘要

在药物发现中,在先导优化和候选表征阶段,经常在一组体外药理学分析中评估新的小分子,以确定与各种受体、转运蛋白、离子通道和酶(包括激酶)的潜在非预期、脱靶相互作用。此外,这些筛选面板还可以在开发的后期提供实用性,以提供对意外安全发现的机械理解。在这里,我们根据对科学文献的广泛整理,将与相互作用相关的最可能的功能和病理结果汇总到一个由95种激酶组成的小组中。这组激酶是AbbVie根据从文献中提取的安全性相关数据以及从发现工作中产生的20多年的机构知识设计的。对于每种激酶,都使用在线数据库对科学文献进行了综述,并总结了最常报道的功能和病理作用。这项工作应作为小分子药物发现科学家和临床研究人员预测和/或解释与这些激酶的药理学相互作用相关的不良反应的实用指南。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Off-target pharmacological activity at various kinases: Potential functional and pathological side effects

In drug discovery, during the lead optimization and candidate characterization stages, novel small molecules are frequently evaluated in a battery of in vitro pharmacology assays to identify potential unintended, off-target interactions with various receptors, transporters, ion channels, and enzymes, including kinases. Furthermore, these screening panels may also provide utility at later stages of development to provide a mechanistic understanding of unexpected safety findings. Here, we present a compendium of the most likely functional and pathological outcomes associated with interaction(s) to a panel of 95 kinases based on an extensive curation of the scientific literature. This panel of kinases was designed by AbbVie based on safety-related data extracted from the literature, as well as from over 20 years of institutional knowledge generated from discovery efforts. For each kinase, the scientific literature was reviewed using online databases and the most often reported functional and pathological effects were summarized. This work should serve as a practical guide for small molecule drug discovery scientists and clinical investigators to predict and/or interpret adverse effects related to pharmacological interactions with these kinases.

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来源期刊
Journal of pharmacological and toxicological methods
Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY
CiteScore
3.60
自引率
10.50%
发文量
56
审稿时长
26 days
期刊介绍: Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.
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