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当代肿瘤药物靶点

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

含咔唑和吡唑类抗癌化合物的潜在靶标和作用机理

卷 20, 期 5, 2020

页: [364 - 371] 页: 8

弟呕挨: 10.2174/1568009620666200115162343

价格: $65

摘要

目标:描述一种小型抗癌化合物。 背景:肿瘤的治疗，只有小分子才能有效地跨越血脑屏障。通过使用传感器结合报告系统同时筛选结肠癌和胶质瘤细胞系，我们选出了一些新的命中点。在此，我们关注其中一个。 目的: 阐明一种新型抗癌化合物的潜在靶点。 方法: 采用计算机辅助结构和基序分析(最小绝对收缩和选择算子或LASSO评分)评估化合物的靶点，然后采用直接激酶活性测定法进行确认;磷酸化激酶的Western blot测定以及流式细胞仪(FACS)和半胱天冬蛋白酶3/7活性测定(caspase 3/7)来解释其作用机制。最后，通过real-time PCR对各种G蛋白通路的蛋白进行表达谱分析。 结果: 小化合物(4E)-4-[2-(9-乙基- 9H-咔唑-3-基)肼-1-叉二]-3-甲基- 4,5-二氢- 1h -吡唑-5- 1，分子式C18H17N5O，分子量为319.36，命名为VUGX01，经计算机分析(最小绝对收缩和选择算子或LASSO评分)预测为受体酪氨酸激酶(RTKs)的配体/抑制剂。然而，重组蛋白激酶的直接分析表明，在1微摩的浓度下，它并不是一种有效的受体激酶抑制剂。该化合物能激活某些肿瘤细胞系的半胱天蛋白酶，但对细胞周期的影响极小。药物治疗导致AKT和c- RAF磷酸化水平以及MAP2K表达水平的变化，提示该化合物可能与G蛋白偶联受体相互作用。real-time PCR对不同G蛋白通路的82个蛋白的表达谱显示，该治疗上调了几种蛋白的表达，包括血管紧张素原、血管紧张素受体和ip3 -激酶催化亚基。 结论: VUGX01能有效阻断某些类型癌细胞的增殖和诱导细胞凋亡，即使有高套索评分的预测，但它不是一种有效的RTKs抑制剂，可能是通过作为一个或多个GPCRs的新配体来抑制细胞生长。

关键词: 凋亡，HTS，药物靶标，半胱天冬蛋白酶，GPCRs，结直肠癌，胶质瘤。

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