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Updated: Jan 1, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Promiscuity analysis of a kinase panel screen with designated p38 alpha inhibitors
Mariana González-Medina1, Filip Miljković1, Gernot S Haase2
1Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Endenicher Allee 19c, D-53115, Bonn, Germany.
Abstract:
Protein phosphorylation by kinases is of critical importance for the regulation of many cellular functions. When kinases are deregulated numerous biological processes are affected, which may cause a variety of diseases. Therefore, kinase inhibition plays an important role for therapeutic intervention. A number of kinase inhibitors have been approved as drugs, initially in oncology where promiscuous (multi-kinase) inhibitors were most efficacious. Exploring kinase inhibitor selectivity and promiscuity for therapy is among the most challenging aspects of kinase drug discovery. Herein, we thoroughly analyze a kinase profiling experiment in which 637 designated inhibitors of p38α MAP kinase (p38α) were tested against a panel of 60 kinases distributed across the human kinome. In this experiment, only 19% of the inhibitors were found to be promiscuous when the median p38α inhibition level was applied as an activity threshold. Promiscuous inhibitors had a median value of two targets per compound, and many of these inhibitors were only active against the p38α and closely related JNK3 enzymes. Promiscuity cliffs were identified and analyzed in a network representation revealing structural modifications that were implicated in triggering compound promiscuity. Taken together, the findings revealed a high degree of selectivity of designated p38α directed inhibitors although they target the ATP binding site that is largely conserved across the human kinome.
Insights
Most kinase inhibitors targeting p38α MAP kinase (p38α) are selective. Analysis of 637 inhibitors revealed that only 19% were promiscuous, often targeting closely related kinases, challenging drug discovery assumptions.
Area of Science:
- Biochemistry
- Pharmacology
- Drug Discovery
Background:
- Kinase phosphorylation regulates crucial cellular functions; dysregulation leads to diseases.
- Kinase inhibitors are vital therapeutics, particularly in oncology, with selectivity and promiscuity being key considerations.
- Understanding kinase inhibitor behavior is critical for effective drug development.
Purpose of the Study:
- To analyze the selectivity and promiscuity of 637 designated p38α MAP kinase (p38α) inhibitors.
- To identify factors contributing to kinase inhibitor promiscuity.
- To assess the therapeutic potential of p38α inhibitors.
Main Methods:
- A kinase profiling experiment was conducted, testing 637 p38α inhibitors against a panel of 60 kinases.
- Inhibitor activity data was analyzed using the median p38α inhibition level as a threshold for promiscuity.
- Network analysis was employed to visualize and understand promiscuity cliffs and structural modifications.
Main Results:
- Only 19% of the tested inhibitors exhibited promiscuity based on the defined threshold.
- Promiscuous inhibitors typically targeted a median of two kinases, frequently including p38α and JNK3.
- Structural analysis revealed modifications associated with increased compound promiscuity.
Conclusions:
- Designated p38α inhibitors demonstrate a high degree of selectivity, contrary to initial assumptions about targeting conserved ATP binding sites.
- The study provides insights into managing kinase inhibitor promiscuity in drug discovery.
- Findings aid in developing more targeted kinase-based therapies.
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