用表面等离子体共振研究激酶抑制剂的化合物选择性和靶点驻留时间
Compound Selectivity and Target Residence Time of Kinase Inhibitors Studied with Surface Plasmon Resonance.
作者信息
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
机构信息
Netherlands Translational Research Center B.V., Oss, the Netherlands.
Carna Biosciences, Inc., Kobe, Japan.
出版信息
J Mol Biol. 2017 Feb 17;429(4):574-586. doi: 10.1016/j.jmb.2016.12.019. Epub 2016 Dec 30.
Target residence time (τ) has been suggested to be a better predictor of the biological activity of kinase inhibitors than inhibitory potency (IC) 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) were calculated to determine kinetic selectivity. Comparison of τ and K or IC 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.
与酶分析中的抑制效力（IC）相比，靶标停留时间（τ）被认为是激酶抑制剂生物活性的更好预测指标。开发了针对46种人类蛋白质和脂质激酶的表面等离子体共振结合分析方法。测定了80种激酶抑制剂相互作用的结合和解离常数。计算τ和平衡亲和常数（K）以确定动力学选择性。τ与K或IC值的比较揭示了对几种激酶抑制剂选择性的截然不同的观点，包括在10种不同激酶上进行测试的多激酶抑制剂波纳替尼。此外，已知的泛极光抑制剂在极光B上的停留时间比在极光A上长得多，尽管它们对极光A和B具有相当的亲和力。此外，γ/δ选择性PI3K抑制剂度维利西布和δ选择性药物idelalisib对δ异构体相对于γ异构体具有相似的20倍选择性，但度维利西布在两个靶标上的停留时间长得多。
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