Applications of promiscuity of FDA-approved kinase inhibitors in drug repositioning and toxicity

Abstract

Promiscuity of therapeutics has important implications in treatment and toxicity. So far, a comprehensive understanding of promiscuity related to kinase inhibitors is lacking and such an analysis may offer potential opportunities for drug repurposing. In the present study, profiling of inhibitor-specific kinases based on the available biochemical IC50s was performed, fold-change of IC50 values for additional targets were calculated by taking the primary target as the reference kinase, and finally the promiscuity degree (PD) for FDA-approved kinase inhibitors was calculated. Surprisingly, class II inhibitors showed more PD than that of the class I inhibitors. We further identified cancer types and sub-types in which additional kinase targets or off-targets of inhibitors were overexpressed for potential drug repurposing. In addition, the expression of these kinases in normal human tissues were also profiled to predict toxicity following drug repositioning. Taken together, the study offers opportunities for cancer treatment in a kinase-specific manner.