1. Promiscuity analysis of a kinase panel screen with designated p38 alpha inhibitors
- Author
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Joerg Trappe, Jürgen Bajorath, Filip Miljković, Peter Drueckes, Stefan Laufer, Mariana González-Medina, and Gernot S. Haase
- Subjects
Pharmacology ,chemistry.chemical_classification ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Drug discovery ,Kinase ,p38 mitogen-activated protein kinases ,Organic Chemistry ,Drug Evaluation, Preclinical ,General Medicine ,Computational biology ,Mitogen-Activated Protein Kinase 14 ,Structure-Activity Relationship ,Enzyme ,chemistry ,Mitogen-activated protein kinase ,Drug Design ,Drug Discovery ,biology.protein ,Humans ,Protein phosphorylation ,Kinome ,Binding site ,Protein Kinase Inhibitors - 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.
- Published
- 2019