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

Large-scale analysis of public human and mouse proteinkinase inhibitor(PKI) data identified more than 155,000 human PKIs (and similar to 3000murine 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 corestructure diversity. Human PKIs included an unexpectedly large numberof nearly 14,000 covalent PKIs (CPKIs), similar to 87% of which containedacrylamide or heterocyclic urea warheads. These CPKIs were activeagainst a large number of 369 human kinases. The promiscuity of PKIsand CPKIs was overall comparable. However, there was a notable enrichmentof acrylamide- but not heterocyclic urea-containing CPKIs among mostpromiscuous inhibitors. Furthermore, CPKIs with both warheads hadsignificantly higher potency than structurally analogous PKIs. Takentogether, these findings have several implications for medicinal chemistrythat are discussed.

Automated summary

Large-scale analysis of public human and mouse protein kinase inhibitor (PKI) data revealed a significant number of human and mouse PKIs with reliable activity measurements. Human PKIs were found to exhibit coverage against a large number of kinases, with a substantial growth in the past years. Covalent PKIs containing acrylamide or heterocyclic urea warheads were particularly abundant, and they showed higher potency compared to structurally analogous PKIs. These findings have important implications for medicinal chemistry.