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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

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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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[1]
(a) Rask-Andersen, M.; Almén, M.S.; Schiöth, H.B. Trends in the exploitation of novel drug targets. Nat. Rev. Drug Discov., 2011, 10(8), 579-590.
[http://dx.doi.org/10.1038/nrd3478] [PMID: 21804595]
(b) Swinney, D.C.; Anthony, J. How were new medicines discovered? Nat. Rev. Drug Discov., 2011, 10(7), 507-519.
[http://dx.doi.org/10.1038/nrd3480] [PMID: 21701501]
[2]
(a) Zheng, W.; Thorne, N.; McKew, J.C. Phenotypic screens as a renewed approach for drug discovery. Drug Discov. Today, 2013, 18(21-22), 1067-1073.
[http://dx.doi.org/10.1016/j.drudis.2013.07.001] [PMID: 23850704]
(b) Sams-Dodd, F. Is poor research the cause of the declining productivity of the pharmaceutical industry? An industry in need of a paradigm shift. Drug Discov. Today, 2013, 18(5-6), 211-217.
[http://dx.doi.org/10.1016/j.drudis.2012.10.010] [PMID: 23131208]
(c) Williams, M. Productivity shortfalls in drug discovery: contributions from the preclinical sciences? J. Pharmacol. Exp. Ther., 2011, 336(1), 3-8.
[http://dx.doi.org/10.1124/jpet.110.171751] [PMID: 20739456]
[3]
Vogt, A.; Lazo, J.S. Chemical complementation: A definitive phenotypic strategy for identifying small molecule inhibitors of elusive cellular targets. Pharmacol. Ther., 2005, 107(2), 212-221.
[http://dx.doi.org/10.1016/j.pharmthera.2005.03.002] [PMID: 15925410]
[4]
Reaume, A.G. Drug repurposing through nonhypothesis driven phenotypic screening. Drug Discov. Today, 2011, 8(3), 4.
[5]
Xie, J.; Wang, C.; Virostko, J.; Manning, H.C.; Pham, W.; Bauer, J.; Gore, J.C. A novel reporter system for molecular imaging and high-throughput screening of anticancer drugs. ChemBioChem, 2013, 14(12), 1494-1503.
[http://dx.doi.org/10.1002/cbic.201300142] [PMID: 23881799]
[6]
Xie, J.; Wang, C.; Gore, J.C. High throughput screening for colorectal cancer specific compounds. Comb. Chem. High Throughput Screen., 2016, 19(3), 180-188.
[http://dx.doi.org/10.2174/1386207319666160202120928] [PMID: 26830359]
[7]
Zalewska, M.; Siara, M.; Sajewicz, W. G protein-coupled receptors: abnormalities in signal transmission, disease states and pharmacotherapy. Acta Pol. Pharm., 2014, 71(2), 229-243.
[PMID: 25272642]
[8]
Liu, Y.; An, S.; Ward, R.; Yang, Y.; Guo, X-X.; Li, W.; Xu, T-R. G protein-coupled receptors as promising cancer targets. Cancer Lett., 2016, 376(2), 226-239.
[http://dx.doi.org/10.1016/j.canlet.2016.03.031] [PMID: 27000991]
[9]
Issa, S.; Prandina, A.; Bedel, N.; Rongved, P.; Yous, S.; Le Borgne, M.; Bouaziz, Z. Carbazole scaffolds in cancer therapy: A review from 2012 to 2018. J. Enzyme Inhib. Med. Chem., 2019, 34(1), 1321-1346.
[http://dx.doi.org/10.1080/14756366.2019.1640692] [PMID: 31328585]
[10]
Sanchez-Martinez, C.; Shih, C.; Faul, M.M.; Zhu, G.; Paal, M.; Somoza, C.; Li, T.; Kumrich, C.A.; Winneroski, L.L.; Xun, Z.; Brooks, H.B.; Patel, B.K.R.; Schultz, R.M.; DeHahn, T.B.; Spencer, C.D.; Watkins, S.A.; Considine, E.; Dempsey, J.A.; Ogg, C.A.; Campbell, R.M.; Anderson, B.A.; Wagner, J. Aryl[a]pyrrolo[3,4-c]carbazoles as selective cyclin D1-CDK4 inhibitors. Bioorg. Med. Chem. Lett., 2003, 13(21), 3835-3839.
[http://dx.doi.org/10.1016/S0960-894X(03)00791-1] [PMID: 14552791]
[11]
Naim, M.J.; Alam, O.; Nawaz, F.; Alam, M.J.; Alam, P. Current status of pyrazole and its biological activities. J. Pharm. Bioallied Sci., 2016, 8(1), 2-17.
[http://dx.doi.org/10.4103/0975-7406.171694] [PMID: 26957862]
[12]
Reid, D.; Sadjad, B.S.; Zsoldos, Z.; Simon, A. LASSO-ligand activity by surface similarity order: a new tool for ligand based virtual screening. J. Comput. Aided Mol. Des., 2008, 22(6-7), 479-487.
[http://dx.doi.org/10.1007/s10822-007-9164-5] [PMID: 18204980]
[13]
Manning, H.C.; Merchant, N.B.; Foutch, A.C.; Virostko, J.M.; Wyatt, S.K.; Shah, C.; McKinley, E.T.; Xie, J.; Mutic, N.J.; Washington, M.K.; LaFleur, B.; Tantawy, M.N.; Peterson, T.E.; Ansari, M.S.; Baldwin, R.M.; Rothenberg, M.L.; Bornhop, D.J.; Gore, J.C.; Coffey, R.J. Molecular imaging of therapeutic response to epidermal growth factor receptor blockade in colorectal cancer. Clin. Cancer Res., 2008, 14(22), 7413-7422.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-0239] [PMID: 19010858]
[14]
Altomare, D.A.; Testa, J.R. Perturbations of the AKT signaling pathway in human cancer. Oncogene, 2005, 24(50), 7455-7464.
[http://dx.doi.org/10.1038/sj.onc.1209085] [PMID: 16288292]
[15]
Jacinto, E.; Facchinetti, V.; Liu, D.; Soto, N.; Wei, S.; Jung, S.Y.; Huang, Q.; Qin, J.; Su, B. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell, 2006, 127(1), 125-137.
[http://dx.doi.org/10.1016/j.cell.2006.08.033] [PMID: 16962653]
[16]
Lappano, R.; Maggiolini, M. G protein-coupled receptors: Novel targets for drug discovery in cancer. Nat. Rev. Drug Discov., 2011, 10(1), 47-60.
[http://dx.doi.org/10.1038/nrd3320] [PMID: 21193867]
[17]
Filardo, E.J.; Quinn, J.A.; Bland, K.I.; Frackelton, A.R., Jr Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol. Endocrinol., 2000, 14(10), 1649-1660.
[http://dx.doi.org/10.1210/mend.14.10.0532] [PMID: 11043579]
[18]
Hart, S.; Fischer, O.M.; Prenzel, N.; Zwick-Wallasch, E.; Schneider, M.; Hennighausen, L.; Ullrich, A. GPCR-induced migration of breast carcinoma cells depends on both EGFR signal transactivation and EGFR-independent pathways. Biol. Chem., 2005, 386(9), 845-855.
[http://dx.doi.org/10.1515/BC.2005.099] [PMID: 16164409]

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