Identification of pyrazine-based TrkA inhibitors: design, synthesis, evaluation, and computational modeling studies
Identification of pyrazine-based TrkA inhibitors: design, synthesis, evaluation, and computational modeling studies
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DOI：
10.1039/c4md00251b
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发表时间：
2014-10-01
期刊：
影响因子：
--
通讯作者：
Li, Hong-yu
中科院分区：
文献类型：
--
作者：
Frett, Brendan;McConnell, Nick;Li, Hong-yu
Trk受体在神经元网络的发育和维持中起关键作用。最近的证据表明，Trk家族，特别是TrkA，是肿瘤生长，炎症和神经性疼痛以及化疗耐药性的重要驱动因素。通过计算机筛选，鉴定了一种新的Trk活性药效团，并开发了一系列基于吡嗪的抑制剂，这些抑制剂有效地抑制TrkA。当针对小的酪氨酸激酶组筛选时，抑制剂显示出对TrkA的最高活性，并且还显示出非线性SAR。研究了抑制剂的预测结合模式，确定了未来开发更先进抑制剂的可开发区域。
Trk receptors play a key role in the development and maintenance of neuronal networks. Recent evidence suggests that the Trk family, specifically TrkA, is an important driver for tumour growth, inflammatory and neuropathic pain, and chemoresistance. Through a computational screen, a novel Trk active pharmacophore was identified and a series of pyrazine-based inhibitors were developed, which potently inhibited TrkA. Inhibitors displayed the highest activity on TrkA when screened against a small, tyrosine kinase panel and also exhibited a non-linear SAR. Predicted binding modes of the inhibitors were examined, which identified exploitable regions for future development of more advanced inhibitors.