基于表观基因组的综合策略,对临床激酶抑制剂进行无偏见的功能分析。

IF 8.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Systems Biology Pub Date : 2024-06-01 Epub Date: 2024-05-09 DOI:10.1038/s44320-024-00040-x
Francesco Gualdrini, Stefano Rizzieri, Sara Polletti, Francesco Pileri, Yinxiu Zhan, Alessandro Cuomo, Gioacchino Natoli
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引用次数: 0

摘要

有 500 多种激酶参与了哺乳动物大多数细胞过程的控制,它们的活性失调与癌症和炎症性疾病有关。目前已有 80 种临床激酶抑制剂(CKIs)获准用于临床,还有数百种激酶抑制剂正处于不同的开发阶段。然而,激酶抑制剂除了抑制预期靶点外,还会抑制其他激酶,这既会增强临床效果,也会产生副作用,而这些副作用只能根据体外选择性分析进行部分预测。在这里,我们报告了一种综合方法,该方法以染色质修饰为基础,将其作为 CKIs 对巨噬细胞活化功能影响的无偏见、信息丰富的读数。这种方法超越了基于转录组的方法,使我们能够识别具有相同预期靶点的 CKI 之间的相似性和差异性,识别新的 CKI 特异性,并确定可重新用于控制炎症的 CKI,从而支持这种策略在临床环境中改善 CKI 的选择和使用。
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An integrative epigenome-based strategy for unbiased functional profiling of clinical kinase inhibitors.

More than 500 kinases are implicated in the control of most cellular process in mammals, and deregulation of their activity is linked to cancer and inflammatory disorders. 80 clinical kinase inhibitors (CKIs) have been approved for clinical use and hundreds are in various stages of development. However, CKIs inhibit other kinases in addition to the intended target(s), causing both enhanced clinical effects and undesired side effects that are only partially predictable based on in vitro selectivity profiling. Here, we report an integrative approach grounded on the use of chromatin modifications as unbiased, information-rich readouts of the functional effects of CKIs on macrophage activation. This approach exceeded the performance of transcriptome-based approaches and allowed us to identify similarities and differences among CKIs with identical intended targets, to recognize novel CKI specificities and to pinpoint CKIs that may be repurposed to control inflammation, thus supporting the utility of this strategy to improve selection and use of CKIs in clinical settings.

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来源期刊
Molecular Systems Biology
Molecular Systems Biology 生物-生化与分子生物学
CiteScore
18.50
自引率
1.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: Systems biology is a field that aims to understand complex biological systems by studying their components and how they interact. It is an integrative discipline that seeks to explain the properties and behavior of these systems. Molecular Systems Biology is a scholarly journal that publishes top-notch research in the areas of systems biology, synthetic biology, and systems medicine. It is an open access journal, meaning that its content is freely available to readers, and it is peer-reviewed to ensure the quality of the published work.
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