Data Sets of Human and Mouse Protein Kinase Inhibitors With Curated Activity Data Including Covalent Inhibitors

Abstract

Aim: Generation of high-quality data sets of protein kinase inhibitors (PKIs). Methodology: Publicly available PKIs with reliable activity data were curated. PKIs with very weak activity were classified as inactive. Analogue series and PKIs containing reactive groups (warheads) enabling covalent inhibition were systematically identified. Exemplary results & data: A total of 155,579 human and 3057 mouse PKIs were obtained. Human PKIs were active 440 kinases and included 13,949 covalent PKIs. The collection of qualifying PKIs and corresponding inactive compounds is made available as an open access deposition. Limitations & next steps: Potential limitations include activity data incompleteness and assay variance. The data set can be used to investigate PKIs with alternative modes of action and calibrate computational methods.

Plain Language Summary

Protein kinases are proteins that play a role in how cells grow. In cancer cells, protein kinases are altered, which can cause abnormal growth. Protein kinase inhibitors (PKIs) specifically target protein kinases and are considered for treating different diseases, like cancer. In this study, we investigated a large number of PKIs that are available to the public to find ones with reliable activity data. We aim to understand how their structure affects their activity, including how these compounds bind to protein kinases. This helps us to identify different types of PKIs. Understanding PKIs is important for both basic research in the protein kinase field and drug discovery.

Graphical abstract

In drug discovery, inhibitors of human kinases are intensively investigated for a variety of therapeutic applications. Shown is a phylogenetic tree representation of the human kinome. Blue dots represent protein kinases for which chemical inhibitors are available. The dots are scaled in size according to the number of inhibitors per kinase. Currently available inhibitors cover more than 80% of the human kinome.

Keywords:

• activity data
• analogue series
• covalent inhibition
• inhibitors
• large-scale data analysis
• protein kinases

Author contributions

J Bajorath conceived the study; E Xerxa carried out the analysis; E Xerxa and J Bajorath analyzed the results; E Xerxa and J Bajorath prepared the manuscript.

Acknowledgments

The authors thank F Miljković and M Vogt for support.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.