Novel small molecule activators of the Trk family of receptor tyrosine kinases.
Novel small molecule activators of the Trk family of receptor tyrosine kinases.
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DOI：
10.1016/j.bbapap.2012.08.021
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发表时间：
2013-10
影响因子：
3.2
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
--
作者：
Obianyo, Obiamaka;Ye, Keqiang
原肌球蛋白相关激酶（Trk）受体是受体酪氨酸激酶家族的一个亚组，在外周和中枢神经系统中具有调节神经营养信号传导的重要功能。由于受体能够通过与它们各自的神经营养因子配体相关联来介导神经元存活，因此许多研究集中在产生小分子模拟化合物的治疗潜力上，所述小分子模拟化合物引起与天然蛋白质配体类似的激动作用。为此，各种基于结构的研究已经导致产生选择性地启动Trk受体信号传导的基于二价肽的激动剂和抗体;然而，这些化合物不具有潜在药物的理想特征。此外，依赖基于结构的数据来产生化合物文库限制了具有所需活性的新型化学结构的潜在鉴定。因此，随后的研究利用基于细胞的凋亡筛选来促进对大的、多样化的小分子化学文库的分析，并快速鉴定具有Trk依赖性抗凋亡活性的化合物。在此，我们描述了Trk激动剂，已确定通过这种筛选方法，并总结其在体外和体内的神经营养活性，以及其在各种神经系统疾病模型的疗效，暗示其未来的效用作为治疗化合物。
The Tropomyosin-related kinase (Trk) receptors are a subset of the receptor tyrosine kinase family with an important functionality in the regulation of neurotrophic signaling in the peripheral and central nervous system. As the receptors are able to mediate neuronal survival by associating with their respective neurotrophin ligands, many studies have focused on the therapeutic potential of generating small-molecule mimetic compounds that elicit agonistic effects similar to those of the natural protein ligands. To this end, various structure-based studies have led to the generation of bivalent peptide-based agonists and antibodies that selectively initiate Trk receptor signaling; however, these compounds do not possess the ideal characteristics of a potential drug. Additionally, the reliance of structure-based data to generate the compound libraries, limits the potential identification of novel chemical structures with desirable activity. Therefore, subsequent investigations utilized a cell-based apoptotic screen to facilitate the analysis of large, diverse chemical libraries of small molecules and quickly identify compounds with Trk-dependent antiapoptotic activity. Herein, we describe the Trk agonists that have been identified by this screening methodology and summarize their in vitro and in vivo neurotrophic activity as well as their efficacy in various neurological disease models, implicating their future utility as therapeutic compounds.
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影响因子：
3.7
作者：
Jang SW;Liu X;Chan CB;France SA;Sayeed I;Tang W;Lin X;Xiao G;Andero R;Chang Q;Ressler KJ;Ye K
通讯作者：
Ye K
影响因子：
4
作者：
Chen, Dianjun;Brahimi, Fouad;Burgess, Kevin
通讯作者：
Burgess, Kevin
影响因子：
5.1
作者：
KHALID, SA;DUDDECK, H;GONZALEZSIERRA, M
通讯作者：
GONZALEZSIERRA, M
影响因子：
3.3
作者：
CLARY, DO;WESKAMP, G;REICHARDT, LF
通讯作者：
REICHARDT, LF
影响因子：
5.3
作者：
Blugeot, Aurelie;Rivat, Cyril;Becker, Chrystel
通讯作者：
Becker, Chrystel