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Updated: Jun 26, 2025
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
An integrative epigenome-based strategy for unbiased functional profiling of clinical kinase inhibitors
Francesco Gualdrini1, Stefano Rizzieri2, Sara Polletti2
1Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milano, 20139, Italy. francesco.gualdrini@ieo.it.
Abstract:
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.
Insights
This study introduces a novel method using chromatin modifications to assess the effects of kinase inhibitors. This approach improves the understanding of drug specificity and identifies potential anti-inflammatory uses for existing kinase inhibitors.
Area of Science:
- Biochemistry
- Pharmacology
- Immunology
Background:
- Kinases regulate cellular processes, and their dysregulation is linked to cancer and inflammation.
- Clinical kinase inhibitors (CKIs) are widely used but often lack target specificity, leading to side effects.
- Current methods for predicting CKI effects have limitations in capturing real-world functional impacts.
Purpose of the Study:
- To develop an unbiased method for evaluating the functional effects of CKIs.
- To compare the efficacy of chromatin modification readouts against transcriptome-based approaches.
- To identify novel specificities and potential anti-inflammatory applications of CKIs.
Main Methods:
- Utilized chromatin modifications as readouts of CKI activity in macrophage activation.
- Integrated multiple data types to analyze CKI functional effects.
- Compared the developed approach with transcriptome-based analyses.
Main Results:
- The chromatin modification approach outperformed transcriptome-based methods in assessing CKI effects.
- Identified similarities and differences among CKIs with the same intended targets.
- Discovered novel specificities for certain CKIs and pinpointed candidates for repurposing in inflammation control.
Conclusions:
- Chromatin modifications offer a powerful, unbiased strategy for assessing CKI functional effects.
- This approach enhances the selection and clinical application of CKIs.
- The findings support the repurposing of CKIs for managing inflammatory conditions.
