Activity-based kinase profiling of approved tyrosine kinase inhibitors

Area of Science:

• Pharmacology
• Biochemistry
• Oncology

Background:

• Tyrosine kinase inhibitors (TKIs) are crucial in targeted cancer therapy.
• Understanding their specificities and off-target effects is vital for optimizing treatment and minimizing adverse events.

Purpose of the Study:

• To comprehensively assess the kinase specificities of nine approved TKIs.
• To correlate kinase activity profiles with in vivo drug concentrations and identify potential off-target effects linked to side effects.

Main Methods:

• Activity-based kinase profiling was performed on a large panel of human kinases (including tyrosine, serine/threonine, lipid, and mutant kinases) using nine approved TKIs.
• Kinase profiling was conducted at both K(m) and physiological ATP concentrations (1 mM).
• Inhibitor IC(50) values were compared with estimated plasma-free concentrations derived from pharmacokinetic data.

Main Results:

• The study identified numerous potential kinase targets for each TKI at K(m) ATP concentrations.
• Profiling at physiological ATP concentrations revealed that approved TKIs are generally well-optimized for their intended targets.
• Off-target kinase activity was implicated as a potential cause of drug side effects.

Conclusions:

• Large-scale kinase profiling at varying ATP concentrations is a valuable approach for characterizing both on-target and off-target activities of TKIs.
• This methodology can aid in predicting and understanding drug efficacy and toxicity.
• The findings support the continued use and development of TKIs in cancer treatment.