Compound Selectivity and Target Residence Time of Kinase Inhibitors Studied with Surface Plasmon Resonance. Issue 4 (17th February 2017)

• Record Type: Journal Article
• Authors: Willemsen-Seegers, Nicole; Uitdehaag, Joost C.M.; Prinsen, Martine B.W.; de Vetter, Judith R.F.; de Man, Jos; Sawa, Masaaki; Kawase, Yusuke; Buijsman, Rogier C.; Zaman, Guido J.R.
• Is Part Of: Journal of molecular biology. Volume 429:Issue 4(2017)
• Page Start: 574
• Page End: 586
• Publication Date: 2017-02-17
• Subjects: FDA US Food and Drug Administration -- EGFR epidermal growth factor receptor -- BTK Bruton's tyrosine kinase -- SPR surface plasmon resonance -- PI3K phosphoinositide 3-kinase -- SD standard deviation -- SE standard error -- PI3K phosphoinositide 3-kinase -- SPR surface plasmon resonance; target residence time -- protein kinases -- lipid kinases -- surface plasmon resonance -- Biacore; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2016.12.019
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: 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 ( K D ) were calculated to determine kinetic selectivity. Comparison of τ and K D 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 abstract: Highlights: 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.