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General Research Article

基于结构的虚拟筛选、分子对接、分子动力学模拟及喹唑啉衍生物抗egfr肿瘤血管生成代谢反应性研究

卷 31, 期 5, 2024

发表于: 19 May, 2023

页: [595 - 619] 页: 25

弟呕挨: 10.2174/0929867330666230309143711

价格: $65

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摘要

背景：表皮生长因子受体(Epidermal growth factor receptor, EGFR/HER-1)及其通过肿瘤血管生成机制在肿瘤发生发展中的作用在非小细胞肺癌、头颈癌、胆管癌和胶质母细胞瘤中普遍存在。先前针对EGFR激酶结构域的致癌活性的治疗受到获得性突变耐药和厄洛替尼等现有药物的副作用的阻碍，这突出了通过基于结构的药物设计开发新的EGFR抑制剂的必要性。 目的：本研究旨在通过基于结构的虚拟筛选、分子对接和分子动力学模拟，开发新型喹唑啉衍生物，以潜在地与EGFR激酶结构域相互作用，阻碍肿瘤血管生成现象。 方法：使用基于结构的虚拟筛选和五种药物相似研究的利平斯基规则从PubChem数据库中检索和过滤喹唑啉衍生物。采用基于分子对接的虚拟筛选方法和分子动力学模拟方法对顶导联进行识别。 结果：经里宾斯基过滤后，共获得1000个喹唑啉衍生物，其中671个化合物具有类药物性质。使用ADME和毒性过滤器进一步过滤得到28种具有良好药代动力学特征的化合物。基于对接的虚拟筛选鉴定出7种化合物的结合评分高于对照药物达可替尼。通过交叉比对结合分数，选择得分最高的3个化合物QU524、QU571和QU297，利用薛定谔大师的Desmond模块进行100 ns间隔的分子动力学模拟研究，了解它们的构象稳定性。 结论：研究结果表明，所选择的喹唑啉先导物比对照药物厄洛替尼具有更好的结合亲和力和构象稳定性。这些化合物还具有良好的药代动力学和药效学特征，并且不违反Lipinski的五限规则。研究结果表明，这些先导物具有靶向EGFR激酶结构域并抑制EGFR相关肿瘤血管生成现象的潜力。

关键词: 肿瘤血管生成，T790M突变，C797S突变，耐药性，代谢反应性，hERG抑制。

« Previous Next »
[1]
Ellis, L.M. Epidermal growth factor receptor in tumor angiogenesis. Hematol. Oncol. Clin. North Am., 2004, 18(5), 1007-1021, viii.
[http://dx.doi.org/10.1016/j.hoc.2004.06.002] [PMID: 15474332]
[2]
Salomon, D.S.; Brandt, R.; Ciardiello, F.; Normanno, N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit. Rev. Oncol. Hematol., 1995, 19(3), 183-232.
[http://dx.doi.org/10.1016/1040-8428(94)00144-I] [PMID: 7612182]
[3]
Shah, A.A.; Kamal, M.A.; Akhtar, S. Tumor angiogenesis and VEGFR-2: Mechanism, pathways and current biological therapeutic interventions. Curr. Drug Metab., 2021, 22(1), 50-59.
[http://dx.doi.org/10.2174/18755453MTEwxNzQ0x] [PMID: 33076807]
[4]
Minder, P.; Zajac, E.; Quigley, J.P.; Deryugina, E.I. EGFR regulates the development and microarchitecture of intratumoral angiogenic vasculature capable of sustaining cancer cell intravasation. Neoplasia, 2015, 17(8), 634-649.
[http://dx.doi.org/10.1016/j.neo.2015.08.002] [PMID: 26408256]
[5]
Sasaki, T.; Hiroki, K.; Yamashita, Y. The role of epidermal growth factor receptor in cancer metastasis and microenvironment. Bio. Med. Res. Int., 2013, 2013, 1-8.
[http://dx.doi.org/10.1155/2013/546318] [PMID: 23986907]
[6]
De Jong, K.P.; Stellema, R.; Karrenbeld, A.; Koudstaal, J.; Gouw, A.S.; Sluiter, W.J.; Peeters, P.M.J.G.; Slooff, M.J.H.; De Vries, E.G.E. Clinical relevance of transforming growth factor? epidermal growth factor receptor, p53, and Ki67 in colorectal liver metastases and corresponding primary tumors. Hepatology, 1998, 28(4), 971-979.
[http://dx.doi.org/10.1002/hep.510280411] [PMID: 9755233]
[7]
Mendelsohn, J. The epidermal growth factor receptor as a target for cancer therapy. Endocr. Relat. Cancer, 2001, 8(1), 3-9.
[http://dx.doi.org/10.1677/erc.0.0080003] [PMID: 11350723]
[8]
Herbst, R.S. Review of epidermal growth factor receptor biology. Int. J. Radiat. Oncol. Biol. Phys., 2004, 59(2)(Suppl.), S21-S26.
[http://dx.doi.org/10.1016/j.ijrobp.2003.11.041] [PMID: 15142631]
[9]
Harris, A.L. Hypoxia - a key regulatory factor in tumour growth. Nat. Rev. Cancer, 2002, 2(1), 38-47.
[http://dx.doi.org/10.1038/nrc704] [PMID: 11902584]
[10]
Suhardja, A.; Hoffman, H. Role of growth factors and their receptors in proliferation of microvascular endothelial cells. Microsc. Res. Tech., 2003, 60(1), 70-75.
[http://dx.doi.org/10.1002/jemt.10245] [PMID: 12500263]
[11]
Ellis, L.; Liu, W.; Ahmad, S.A.; Fan, F.; Jung, Y.D.; Shaheen, R.M.; Reinmuth, N. Overview of angiogenesis: Biologic implications for antiangiogenic therapy. Semin. Oncol., 2001, 28(5)(Suppl. 16), 94-104.
[http://dx.doi.org/10.1016/S0093-7754(01)90287-8] [PMID: 11706401]
[12]
Fidler, I.J.; Yano, S.; Zhang, R.; Fujimaki, T.; Bucana, C.D. The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol., 2002, 3(1), 53-57.
[http://dx.doi.org/10.1016/S1470-2045(01)00622-2] [PMID: 11905606]
[13]
Iqbal, S.; Lenz, H.J. Integration of novel agents in the treatment of colorectal cancer. Cancer Chemother. Pharmacol., 2004, 54(Suppl. 1), S32-S39.
[http://dx.doi.org/10.1007/s00280-004-0884-0] [PMID: 15309512]
[14]
Langley, R.R.; Fan, D.; Tsan, R.Z.; Rebhun, R.; He, J.; Kim, S.J.; Fidler, I.J. Activation of the platelet-derived growth factor-receptor enhances survival of murine bone endothelial cells. Cancer Res., 2004, 64(11), 3727-3730.
[http://dx.doi.org/10.1158/0008-5472.CAN-03-3863] [PMID: 15172974]
[15]
Kim, S.J.; Uehara, H.; Karashima, T.; Shepherd, D.L.; Killion, J.J.; Fidler, I.J. Blockade of epidermal growth factor receptor signaling in tumor cells and tumor-associated endothelial cells for therapy of androgen-independent human prostate cancer growing in the bone of nude mice. Clin. Cancer Res., 2003, 9(3), 1200-1210.
[PMID: 12631626]
[16]
Sasaki, T.; Nakamura, T.; Rebhun, R.B.; Cheng, H.; Hale, K.S.; Tsan, R.Z.; Fidler, I.J.; Langley, R.R. Modification of the primary tumor microenvironment by transforming growth factor alpha-epidermal growth factor receptor signaling promotes metastasis in an orthotopic colon cancer model. Am. J. Pathol., 2008, 173(1), 205-216.
[http://dx.doi.org/10.2353/ajpath.2008.071147] [PMID: 18583324]
[17]
Liu, T.C.; Jin, X.; Wang, Y.; Wang, K. Role of epidermal growth factor receptor in lung cancer and targeted therapies. Am. J. Cancer Res., 2017, 7(2), 187-202.
[PMID: 28337370]
[18]
Larsen, A.K.; Ouaret, D.; El Ouadrani, K.; Petitprez, A. Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis. Pharmacol. Ther., 2011, 131(1), 80-90.
[http://dx.doi.org/10.1016/j.pharmthera.2011.03.012] [PMID: 21439312]
[19]
Niu, G.; Wright, K.L.; Huang, M.; Song, L.; Haura, E.; Turkson, J.; Zhang, S.; Wang, T.; Sinibaldi, D.; Coppola, D.; Heller, R.; Ellis, L.M.; Karras, J.; Bromberg, J.; Pardoll, D.; Jove, R.; Yu, H. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene, 2002, 21(13), 2000-2008.
[http://dx.doi.org/10.1038/sj.onc.1205260] [PMID: 11960372]
[20]
Forsythe, J.A.; Jiang, B.H.; Iyer, N.V.; Agani, F.; Leung, S.W.; Koos, R.D.; Semenza, G.L. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol., 1996, 16(9), 4604-4613.
[http://dx.doi.org/10.1128/MCB.16.9.4604] [PMID: 8756616]
[21]
Corrado, C.; Fontana, S. Hypoxia and HIF signaling: One axis with divergent effects. Int. J. Mol. Sci., 2020, 21(16), 5611.
[http://dx.doi.org/10.3390/ijms21165611] [PMID: 32764403]
[22]
Del Re, M.; Crucitta, S.; Gianfilippo, G.; Passaro, A.; Petrini, I.; Restante, G.; Michelucci, A.; Fogli, S.; de Marinis, F.; Porta, C.; Chella, A.; Danesi, R. Understanding the mechanisms of resistance in EGFR-positive NSCLC: From tissue to liquid biopsy to guide treatment strategy. Int. J. Mol. Sci., 2019, 20(16), 3951.
[http://dx.doi.org/10.3390/ijms20163951] [PMID: 31416192]
[23]
Harvey, R.D.; Adams, V.R.; Beardslee, T.; Medina, P. Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings. J. Oncol. Pharm. Pract., 2020, 26(6), 1461-1474.
[http://dx.doi.org/10.1177/1078155220931926] [PMID: 32567494]
[24]
Pan, P.C.; Magge, R.S. Mechanisms of EGFR resistance in glioblastoma. Int. J. Mol. Sci., 2020, 21(22), 8471.
[http://dx.doi.org/10.3390/ijms21228471] [PMID: 33187135]
[25]
Fu, K.; Xie, F.; Wang, F.; Fu, L. Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance. J. Hematol. Oncol., 2022, 15(1), 173.
[http://dx.doi.org/10.1186/s13045-022-01391-4] [PMID: 36482474]
[26]
Yun, C.H.; Mengwasser, K.E.; Toms, A.V.; Woo, M.S.; Greulich, H.; Wong, K.K.; Meyerson, M.; Eck, M.J. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. USA, 2008, 105(6), 2070-2075.
[http://dx.doi.org/10.1073/pnas.0709662105] [PMID: 18227510]
[27]
Hossam, M.; Lasheen, D.S.; Abouzid, K.A.M. Covalent EGFR inhibitors: Binding mechanisms, synthetic approaches, and clinical profiles. Arch. Pharm., 2016, 349(8), 573-593.
[http://dx.doi.org/10.1002/ardp.201600063] [PMID: 27258393]
[28]
Arrieta, O.; Vega-González, M.T.; López-Macías, D.; Martínez-Hernández, J.N.; Bacon-Fonseca, L.; Macedo-Pérez, E.O.; Ramírez-Tirado, L.A.; Flores-Estrada, D.; de la Garza-Salazar, J. Randomized, open-label trial evaluating the preventive effect of tetracycline on afatinib induced-skin toxicities in non-small cell lung cancer patients. Lung Cancer, 2015, 88(3), 282-288.
[http://dx.doi.org/10.1016/j.lungcan.2015.03.019] [PMID: 25882778]
[29]
Piotrowska, Z.; Isozaki, H.; Lennerz, J.K.; Gainor, J.F.; Lennes, I.T.; Zhu, V.W.; Marcoux, N.; Banwait, M.K.; Digumarthy, S.R.; Su, W.; Yoda, S.; Riley, A.K.; Nangia, V.; Lin, J.J.; Nagy, R.J.; Lanman, R.B.; Dias-Santagata, D.; Mino-Kenudson, M.; Iafrate, A.J.; Heist, R.S.; Shaw, A.T.; Evans, E.K.; Clifford, C.; Ou, S.I.; Wolf, B.; Hata, A.N.; Sequist, L.V. Landscape of acquired resistance to osimertinib in EGFR-Mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion. Cancer Discov., 2018, 8(12), 1529-1539.
[http://dx.doi.org/10.1158/2159-8290.CD-18-1022] [PMID: 30257958]
[30]
Wang, S.; Song, Y.; Liu, D. EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett., 2017, 385, 51-54.
[http://dx.doi.org/10.1016/j.canlet.2016.11.008] [PMID: 27840244]
[31]
Grabe, T.; Lategahn, J.; Rauh, D. C797S resistance: The undruggable EGFR mutation in non-small cell lung cancer? ACS Med. Chem. Lett., 2018, 9(8), 779-782.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00314] [PMID: 30128066]
[32]
Bowers, K.J. Scalable algorithms for molecular dynamics simulations on commodity clusters. SC ’06: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing, Tampa, FL, USA, 2006.
[http://dx.doi.org/10.1109/SC.2006.54]
[33]
Bharadwaj, S.; El-Kafrawy, S.A.; Alandijany, T.A.; Bajrai, L.H.; Shah, A.A.; Dubey, A.; Sahoo, A.K.; Yadava, U.; Kamal, M.A.; Azhar, E.I.; Kang, S.G.; Dwivedi, V.D. Structure-based identification of natural products as SARS-CoV-2 Mpro antagonist from Echinacea angustifolia using computational approaches. Viruses, 2021, 13(2), 305.
[http://dx.doi.org/10.3390/v13020305] [PMID: 33672054]

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