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

被引：39

作者：

Willemsen-Seegers, Nicole ^{[1
]}

Uitdehaag, Joost C. M. ^{[1
]}

Prinsen, Martine B. W. ^{[1
]}

de Vetter, Judith R. F. ^{[1
]}

de Man, Jos ^{[1
]}

Sawa, Masaaki ^{[2
]}

Kawase, Yusuke ^{[2
]}

Buijsman, Rogier C. ^{[1
]}

Zaman, Guido J. R. ^{[1
]}

机构：

[1] Netherlands Translat Res Ctr BV, Oss, Netherlands

[2] Carna Biosci Inc, Kobe, Hyogo, Japan

来源：

JOURNAL OF MOLECULAR BIOLOGY | 2017年 / 429卷 / 04期

关键词：

target residence time; protein kinases; lipid kinases; surface plasmon resonance; Biacore; ORALLY BIOAVAILABLE INHIBITOR; SMALL-MOLECULE INHIBITOR; AURORA-A KINASE; PHOSPHOINOSITIDE; 3-KINASE; ANTITUMOR-ACTIVITY; IRREVERSIBLE INHIBITORS; CELLULAR-ACTIVITY; TYROSINE KINASE; IN-VIVO; AMG; 900;

D O I：

10.1016/j.jmb.2016.12.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Target residence time (T) 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. T and equilibrium affinity constants (K-D) were calculated to determine kinetic selectivity. Comparison of T 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 gamma/delta-selective PI3K inhibitor duvelisib and the 6-selective drug idelalisib had similar 20-fold selectivity for delta- over gamma-isoform but duvelisib resided much longer on both targets. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：574 / 586

页数：13

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