title: Compound Selectivity and Target Residence Time of Kinase Inhibitors Studied with Surface Plasmon Resonance.
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 (KD) were calculated to determine kinetic selectivity. Comparison of τ and KDor IC50values 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.
authors.affiliation: Netherlands Translational Research Center B.V., Oss, the Netherlands.
authors.forename: Nicole
authors.initials: N
authors.lastname: Willemsen-Seegers
authors.affiliation: Netherlands Translational Research Center B.V., Oss, the Netherlands.
authors.forename: Joost C M
authors.initials: JCM
authors.lastname: Uitdehaag
authors.affiliation: Netherlands Translational Research Center B.V., Oss, the Netherlands.
authors.forename: Martine B W
authors.initials: MBW
authors.lastname: Prinsen
authors.affiliation: Netherlands Translational Research Center B.V., Oss, the Netherlands.
authors.forename: Judith R F
authors.initials: JRF
authors.lastname: de Vetter
authors.affiliation: Netherlands Translational Research Center B.V., Oss, the Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: de Man
authors.affiliation: Carna Biosciences, Inc., Kobe, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sawa
authors.affiliation: Carna Biosciences, Inc., Kobe, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kawase
authors.affiliation: Netherlands Translational Research Center B.V., Oss, the Netherlands.
authors.forename: Rogier C
authors.initials: RC
authors.lastname: Buijsman
authors.affiliation: Netherlands Translational Research Center B.V., Oss, the Netherlands. Electronic address: guido.zaman@ntrc.nl.
authors.forename: Guido J R
authors.initials: GJR
authors.lastname: Zaman
mesh_terms: D000818:Animals; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007313:Insecta / Q000166:cytology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000378:metabolism*; D020349:Surface Plasmon Resonance
chemical_list: D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human
keywords: Biacore; lipid kinases; protein kinases; surface plasmon resonance; target residence time