Protein kinases (PKs) are involved in many intracellular signal transduction pathways through phosphorylation cascades and have become intensely investigated pharmaceutical targets over the past two decades. Inhibition of PKs using small-molecular inhibitors is a premier strategy for the treatment of diseases in different therapeutic areas that are caused by uncontrolled PK-mediated phosphorylation and aberrant signaling. Most PK inhibitors (PKIs) are directed against the ATP cofactor binding site that is largely conserved across the human kinome comprising 518 wild-type PKs (and many mutant forms). Hence, these PKIs often have varying degrees of multi-PK activity (promiscuity) that is also influenced by factors such as single-site mutations in the cofactor binding region, compound binding kinetics, and residence times. The promiscuity of PKIs is often-but not always-critically important for therapeutic efficacy through polypharmacology. Various in vitro and in vivo studies have also indicated that PKIs have the potential of interacting with additional targets other than PKs, and different secondary cellular targets of individual PKIs have been identified on a case-by-case basis. Given the strong interest in PKs as drug targets, a wealth of PKIs from medicinal chemistry and their activity data from many assays and biological screens have become publicly available over the years. On the basis of these data, for the first time, we conducted a systematic search for non-PK targets of PKIs across the human kinome. Starting from a pool of more than 155,000 curated human PKIs, our large-scale analysis confirmed secondary targets from diverse protein classes for 447 PKIs on the basis of high-confidence activity data. These PKIs were active against 390 human PKs, covering all kinase groups of the kinome and 210 non-PK targets, which included other popular pharmaceutical targets as well as currently unclassified proteins. The target distribution and promiscuity of the 447 PKIs were determined, and different interaction profiles with PK and non-PK targets were identified. As a part of our study, the collection of PKIs with activity against non-PK targets and the associated information are made freely available.
Keywords: activity data; human kinome; kinase inhibitors; multi-target activity; non-kinase targets; protein kinases.