Compound Selectivity and Target Residence Time of Kinase Inhibitors Studied with Surface Plasmon Resonance

•Resource of on- and off-rates of important kinase inhibitor drug interactions•Analysis of the binding of irreversible tyrosine kinase inhibitors in real time•Known “pan”-Aurora kinase inhibitors reside longer on Aurora B than Aurora A.•Idelalisib and duvelisib have same selectivity for δ- over γ-isoform PI3K.

Target residence time (τ) has been suggested to be a better predictor of the biological activity of kinase inhibitors than inhibitory potency (IC50) in enzyme assays. Surface plasmon resonance binding assays for 46 human protein and lipid kinases were developed. The association and dissociation constants of 80 kinase inhibitor interactions were determined. τ and equilibrium affinity constants (KD) were calculated to determine kinetic selectivity. Comparison of τ and KD or IC50 values revealed a strikingly different view on the selectivity of several kinase inhibitors, including the multi-kinase inhibitor ponatinib, which was tested on 10 different kinases. In addition, known pan-Aurora inhibitors resided much longer on Aurora B than on Aurora A, despite having comparable affinity for Aurora A and B. Furthermore, the γ/δ-selective PI3K inhibitor duvelisib and the δ-selective drug idelalisib had similar 20-fold selectivity for δ- over γ-isoform but duvelisib resided much longer on both targets.

Graphical abstractDownload high-res image (170KB)Download full-size image