Various off-target kinases

Various off-target kinases refers to the collective group of protein kinases that are unintentionally modulated by a pharmacological agent, typically a small-molecule kinase inhibitor (TKI). Because the human kinome consists of over 500 enzymes with highly conserved ATP-binding domains, achieving absolute selectivity is challenging, and many drugs exhibit promiscuity by binding to kinases outside their intended therapeutic target (Nature Reviews Drug Discovery, 2018). These off-target interactions are a primary driver of clinical toxicity, such as cardiotoxicity, hepatotoxicity, and myelosuppression, which can limit the therapeutic window of a compound (Journal of Clinical Investigation, 2018). Conversely, in some instances, off-target activity contributes to the overall clinical efficacy of a drug, a phenomenon known as polypharmacology (Science Signaling, 2010). Kinome-wide profiling and phosphoproteomics are standard techniques used during drug development to map these interactions and predict potential safety concerns before clinical trials (PubMed, 2021). Understanding the off-target profile is critical for differentiating between the therapeutic effects and the adverse event profile of multi-kinase inhibitors.

Other names

Off-target kinomeKinome cross-reactivityUnintended kinase targetsPromiscuous kinase inhibitionPolypharmacology targets

Unintended competitive or non-competitive inhibition of ATP-binding sites or allosteric sites across the kinome, leading to the disruption of non-therapeutic signaling pathways.