Multiplex quantitative assays indicate a need for re-evaluating reported small-molecule TrkB agonists
Multiplex quantitative assays indicate a need for re-evaluating reported small-molecule TrkB agonists
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DOI：
10.1126/scisignal.aal1670
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发表时间：
2017-08-22
影响因子：
7.3
通讯作者：
Sames, Dalibor
中科院分区：
文献类型：
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作者：
Boltaev, Umed;Meyer, Yves;Sames, Dalibor
脑源性神经营养因子（BDNF）及其受体原肌球蛋白相关激酶B（Trk B）已成为脑可塑性的关键调节因子，并代表了包括阿尔茨海默病和重度抑郁症在内的多种脑疾病的疾病修饰靶点。由于BDNF的不良药代动力学性质，对小分子TrkB激动剂和调节剂的兴趣很高。已经报道了几种化合物作为TrkB激动剂，并且它们在各种神经系统疾病模型中的日益增加的使用产生了这些是可靠探针的感觉。为了详细研究这些化合物的关键药理学参数，我们开发并优化了一系列互补的定量分析，这些分析可以测量TrkB受体激活、TrkB依赖性下游信号传导和不同细胞环境中的基因表达。虽然BDNF和其他神经营养因子引起了强大的和剂量依赖性的受体激活和下游信号传导，我们无法重现这些活动使用报告的小分子TrkB激动剂。我们的研究结果表明，这些化合物获得的实验结果必须仔细解释，并强调开发可靠的药理学激活剂的这一关键分子靶点的挑战。
Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), have emerged as key regulators of brain plasticity and represent disease-modifying targets for several brain disorders, including Alzheimer's disease and major depressive disorder. Because of poor pharmacokinetic properties of BDNF, the interest in small-molecule TrkB agonists and modulators is high. Several compounds have been reported to act as TrkB agonists, and their increasing use in various nervous system disorder models creates the perception that these are reliable probes. To examine key pharmacological parameters of these compounds in detail, we have developed and optimized a series of complementary quantitative assays that measure TrkB receptor activation, TrkB-dependent downstream signaling, and gene expression in different cellular contexts. Although BDNF and other neurotrophic factors elicited robust and dose-dependent receptor activation and downstream signaling, we were unable to reproduce these activities using the reported small-molecule TrkB agonists. Our findings indicate that experimental results obtained with these compounds must be carefully interpreted and highlight the challenge of developing reliable pharmacological activators of this key molecular target.