Deconvoluting Kinase Inhibitor Induced Cardiotoxicity.
Deconvoluting Kinase Inhibitor Induced Cardiotoxicity.
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DOI：
10.1093/toxsci/kfx082
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发表时间：
2017-07-01
期刊：
影响因子：
--
通讯作者：
Peters MF
中科院分区：
文献类型：
--
作者：
Lamore SD;Ahlberg E;Boyer S;Lamb ML;Hortigon-Vinagre MP;Rodriguez V;Smith GL;Sagemark J;Carlsson L;Bates SM;Choy AL;Stålring J;Scott CW;Peters MF
许多旨在抑制激酶的药物的临床应用受到心脏毒性相关标签警告或处方限制的限制。虽然这种缺陷被广泛认识，但设计更安全的激酶抑制剂（KI）需要了解致病激酶(s)。解开激酶的努力遇到了药理学几乎令人望而却步的复杂性。在与治疗相关的浓度下，KIs在整个基因组中表现出混杂性。在这里，为了克服这种复杂性，我们评估了65个已知的激酶尺度多药理学特征的KIs对心肌细胞（CM）跳动的影响。使用无标记细胞阻抗测量人iPSC-CM的心跳速率和振幅的变化。通过计算分析（Matthews相关系数）来确定相关的激酶，从而挖掘出beat效应和激酶抑制谱之间的相关性。30种激酶符合以下标准：(1)与CM跳动变化相关的药理学抑制，(2)在人诱导的多能干细胞衍生的心肌细胞和成人心脏组织中表达，以及(3)单基因敲除后对CM跳动的影响。这30个激酶的一个子集被选择进行机械随访。我们确定了跨越兴奋-收缩级联的激酶调节过程的例子，包括钙通量（RPS6KA3， IKBKE）和动作电位持续时间（MAP4K2）。最后，建立了一个简单的模型来预测功能性心脏毒性，其中三种前哨激酶（RPS6KB1， FAK, STK35）的失活在体外显示出异常的准确性，并转化为临床KI安全性数据。对于药物发现，确定致病激酶和引入预测模型应该改变设计更安全的KI药物的能力。对于心血管生物学，发现以前未被认识到的影响心血管生物学的激酶应该刺激对未被重视的信号通路的研究。
Many drugs designed to inhibit kinases have their clinical utility limited by cardiotoxicity-related label warnings or prescribing restrictions. While this liability is widely recognized, designing safer kinase inhibitors (KI) requires knowledge of the causative kinase(s). Efforts to unravel the kinases have encountered pharmacology with nearly prohibitive complexity. At therapeutically relevant concentrations, KIs show promiscuity distributed across the kinome. Here, to overcome this complexity, 65 KIs with known kinome-scale polypharmacology profiles were assessed for effects on cardiomyocyte (CM) beating. Changes in human iPSC-CM beat rate and amplitude were measured using label-free cellular impedance. Correlations between beat effects and kinase inhibition profiles were mined by computation analysis (Matthews Correlation Coefficient) to identify associated kinases. Thirty kinases met criteria of having (1) pharmacological inhibition correlated with CM beat changes, (2) expression in both human-induced pluripotent stem cell-derived cardiomyocytes and adult heart tissue, and (3) effects on CM beating following single gene knockdown. A subset of these 30 kinases were selected for mechanistic follow up. Examples of kinases regulating processes spanning the excitation–contraction cascade were identified, including calcium flux (RPS6KA3, IKBKE) and action potential duration (MAP4K2). Finally, a simple model was created to predict functional cardiotoxicity whereby inactivity at three sentinel kinases (RPS6KB1, FAK, STK35) showed exceptional accuracy in vitro and translated to clinical KI safety data. For drug discovery, identifying causative kinases and introducing a predictive model should transform the ability to design safer KI medicines. For cardiovascular biology, discovering kinases previously unrecognized as influencing cardiovascular biology should stimulate investigation of underappreciated signaling pathways.
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影响因子：
46.9
作者：
通讯作者：
--
DOI：
10.1093/database/bau034
发表时间：
2014
期刊：
Database : the journal of biological databases and curation
影响因子：
--
作者：
Huang KY;Wu HY;Chen YJ;Lu CT;Su MG;Hsieh YC;Tsai CM;Lin KI;Huang HD;Lee TY;Chen YJ
通讯作者：
Chen YJ
影响因子：
20.1
作者：
Rose, Robert A.;Kabir, M. Golam;Backx, Peter H.
通讯作者：
Backx, Peter H.
DOI：
10.1085/jgp.201210806
发表时间：
2012-08
期刊：
The Journal of general physiology
影响因子：
--
作者：
Kruse M;Hammond GR;Hille B
通讯作者：
Hille B
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y