Design, synthesis and biological evaluation of 3-(imidazo[1,2-a] pyrazin-3-ylethynyl)-2-methylbenzamides as potent and selective pan-tropomyosin receptor kinase (TRK) inhibitors
Design, synthesis and biological evaluation of 3-(imidazo[1,2-a] pyrazin-3-ylethynyl)-2-methylbenzamides as potent and selective pan-tropomyosin receptor kinase (TRK) inhibitors
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3-(咪唑并[1,2-a]吡嗪-3-乙炔基)-2-甲基苯甲酰胺作为有效和选择性泛原肌球蛋白受体激酶 (TRK) 抑制剂的设计、合成和生物学评价
DOI：
10.1016/j.ejmech.2019.06.064
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发表时间：
2019-10-01
影响因子：
6.7
通讯作者：
Ding, Ke
中科院分区：
文献类型：
--
作者：
Cui, Shengyang;Wang, Yongjin;Ding, Ke
采用结构导向优化策略，设计合成了一系列3-（咪唑并[1，2-a]吡嗪-3-基乙炔基）-2-甲基苯甲酰胺类原肌球蛋白受体激酶（Trks）抑制剂。最有效的化合物之一90抑制TrkA/B/C，IC 50值分别为2.65、10.47和2.95 nM。该化合物剂量依赖性地抑制脑源性神经营养因子（BDNF）介导的TrkB活化，并抑制表达高水平TrkB的SH-SY 5 Y-TrkB神经母细胞瘤细胞的迁移和侵袭。抑制剂90还抑制SH-SY 5 Y-TrkB细胞的增殖，IC 50值为58 nM，与美国FDA最近批准的药物LOXO-101相当。化合物90可作为新的先导化合物用于进一步的抗癌药物发现。(C)2019 Elsevier Masson SAS。All rights reserved.
A series of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides was designed and synthesized as new tropomyosin receptor kinases (Trks) inhibitors by utilizing a structure-guided optimization strategy. One of the most potent compounds 90 suppressed TrkA/B/C with IC50 values of 2.65, 10.47 and 2.95 nM, respectively. The compound dose-dependently inhibited brain-derived neurotrophic factor (BDNF)-mediated TrkB activation and suppressed migration and invasion of SH-SY5Y-TrkB neuroblastoma cells expressing high level of TrkB. Inhibitor 90 also inhibited the proliferation of SH-SY5Y-TrkB cells with an IC50 value of 58 nM, which was comparable to that of an US FDA recently approved drug LOXO-101. Compound 90 may serve as a new lead compound for further anti-cancer drug discovery. (C) 2019 Elsevier Masson SAS. All rights reserved.