Data-Driven Global Assessment of Protein Kinase Inhibitors with Emphasis on Covalent Compounds

Large-scale analysis of public human and mouse protein kinase inhibitor (PKI) data identified more than 155,000 human PKIs (and ∼3000 murine PKIs), for which reliable activity measurements were available. Human PKIs were active against 440 kinases (85% coverage of the kinome). Over the past years, there has been substantial growth of human PKIs, dominated by inhibitors with single-kinase annotations and high core structure diversity. Human PKIs included an unexpectedly large number of nearly 14,000 covalent PKIs (CPKIs), ∼87% of which contained acrylamide or heterocyclic urea warheads. These CPKIs were active against a large number of 369 human kinases. The promiscuity of PKIs and CPKIs was overall comparable. However, there was a notable enrichment of acrylamide- but not heterocyclic urea-containing CPKIs among most promiscuous inhibitors. Furthermore, CPKIs with both warheads had significantly higher potency than structurally analogous PKIs. Taken together, these findings have several implications for medicinal chemistry that are discussed.