Off-target pharmacological activity at various kinases: Potential functional and pathological side effects

In drug discovery, during the lead optimization and candidate characterization stages, novel small molecules are frequently evaluated in a battery of in vitro pharmacology assays to identify potential unintended, off-target interactions with various receptors, transporters, ion channels, and enzymes, including kinases. Furthermore, these screening panels may also provide utility at later stages of development to provide a mechanistic understanding of unexpected safety findings. Here, we present a compendium of the most likely functional and pathological outcomes associated with interaction(s) to a panel of 95 kinases based on an extensive curation of the scientific literature. This panel of kinases was designed by AbbVie based on safety-related data extracted from the literature, as well as from over 20 years of institutional knowledge generated from discovery efforts. For each kinase, the scientific literature was reviewed using online databases and the most often reported functional and pathological effects were summarized. This work should serve as a practical guide for small molecule drug discovery scientists and clinical investigators to predict and/or interpret adverse effects related to pharmacological interactions with these kinases.

Automated summary

In the process of drug discovery, potential unintended off-target interactions between novel small molecules and various receptors, transporters, ion channels, and enzymes (including kinases) are evaluated through a series of in vitro pharmacology assays during the lead optimization and candidate characterization stages. These screening panels can also be used in later stages of development to gain mechanistic understanding of unexpected safety findings.