一种新的MDM2-p53信号通路抑制剂的研究
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摘要
本研究以研发新型小分子MDM2抑制剂为目的,建立了以分子对接为基础的虚拟筛选流程.利用虚拟筛选流程对SPECS化合物库的分子进行类药性筛选、分子对接粗筛、二次筛选以及排序挑选,并通过细胞实验验证这些分子激活p53并抑制肿瘤细胞生长的活性.结果表明M12能够激活p53及其下游信号通路,抑制肿瘤细胞周期并促进肿瘤细胞凋亡.M12与已知MDM2-p53抑制剂结构完全不同,是一种潜在的癌症治疗候选药物.
In this study we employed a docking approach based on virtual screening to search for inhibitors that can bind to MDM2 and block MDM2-p53 interaction. Candidate compounds were obtained from SPECS library. We processed two rounds of molecular docking. Putative compounds were selected based on binding score ranking and 3 D structure inspection. Furthermore, the selected small molecules were validated by cell-based experiments. Treatment of several cancer cells with M12 led to activating p53, and upregulation of p21, leading to cell cycle arrest and apoptosis. To this end, we discovered a novel small molecule named M12 that is structurally different from the known MDM2 antagonists, M12 may be a novel small compound and a potentially useful drug candidate for cancer treatment.
In this study we employed a docking approach based on virtual screening to search for inhibitors that can bind to MDM2 and block MDM2-p53 interaction. Candidate compounds were obtained from SPECS library. We processed two rounds of molecular docking. Putative compounds were selected based on binding score ranking and 3 D structure inspection. Furthermore, the selected small molecules were validated by cell-based experiments. Treatment of several cancer cells with M12 led to activating p53, and upregulation of p21, leading to cell cycle arrest and apoptosis. To this end, we discovered a novel small molecule named M12 that is structurally different from the known MDM2 antagonists, M12 may be a novel small compound and a potentially useful drug candidate for cancer treatment.
引文
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[17] Meng X, Franklin D A, Dong J H, et al. MDM2-p53 pathway in hepatocellular carcinoma [J]. Cancer Res, 2014, 74: 7161.
[18] Barone G, Tweddle D, Shohet J, et al. MDM2-p53 interaction in paediatric solid tumours: preclinical rationale, biomarkers and resistance [J]. Curr Drug Targets, 2014, 15: 114.
[19] Ding Q, Zhang Z M, Liu J J, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development [J]. J Med Chem, 2013, 56: 5979.
[20] Wang S, Wei S, Zhao Y J, et al. SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression [J]. Cancer Res, 2014, 74: 5855.
[21] Sun D, Li Z H, Rew Y, et al. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development [J]. J Med Chem, 2014, 57: 1454.
[22] Shangary S, Wang S. Targeting the MDM2-p53 interaction for cancer therapy [J]. Clin Cancer Res, 2008, 14: 5318.
[23] Koblish H K, Zhao S, Franks C F, et al. Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo [J]. Mol Cancer Ther, 2006, 5: 160.
[24] Lang P T, Brozell S R, Mukherjee S, et al. DOCK 6: combining techniques to model RNA-small molecule complexes [J]. RNA, 2009, 15: 1219.
[25] Trott O, Olson A J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading [J]. J Comput Chem, 2010, 31: 455.
[26] Xiao Z X, Chen J, Levine A J, et al. Interaction between the retinoblastoma protein and the oncoproteinMDM2 [J]. Nature, 1995, 375: 694.
[27] Du W, Wu J F, Walsh E M, et al. Nutlin-3 affects erxpression and function of retinoblastoma protein [J]. J Biol Chem, 2009, 284: 26315.
[2] 谢一, 王阳, 肖智雄. 具有激活RB蛋白生物活性小肽的研究 [J]. 四川大学学报: 自然科学版, 2016, 53: 883.
[3] Zhao Y J, Aguilar A, Bernard D, et al. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment [J]. J Med Chem, 2015, 58: 1038.
[4] Nag S, Zhang X, Srivenugopal, et al. Targeting MDM2-p53 interaction for cancer therapy: are we there yet [J]. Curr Med Chem, 2014, 21: 553.
[5] Zhang B, Golding B T, Hardcastle I R. Small-molecule MDM2-p53 inhibitors: recent advances [J]. Future Med Chem, 2015, 7: 631.
[6] Shangary S, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy [J]. Annu Rev Pharmacol Toxicol, 2009, 49: 223.
[7] Van M T, Rihani A, Van G, et al. Pharmacologic activation of wild-type p53 by nutlin therapy in childhood cancer [J]. Cancer Lett, 2014, 344: 157.
[8] Liu L, Bernard D, Wang S. Case study: discovery of inhibitors of the MDM2-p53 protein-protein interaction [J]. Methods Mol Biol, 2015.1278: 567.
[9] Tazawa H, Kagawa S, Fujiwara T. Advances in adenovirus-mediated p53 cancer gene therapy [J]. Expert Opin Biol Ther, 2013, 13: 1569.
[10] Lukin D J, Carvajal L A, Liu W J, et al. p53 Promotes cell survival due to the reversibility of its cell-cycle checkpoints [J]. Mol Cancer Res, 2015, 13: 16.
[11] Speidel D. The role of DNA damage responses in p53 biology [J]. Arch Toxicol, 2015, 89:501.
[12] Rufini A, Tucci P, Celardo I, et al. Senescence and aging: the critical roles of p53 [J]. Oncogene, 2013, 32: 5129.
[13] Liu J, Zhang C, Hu W, et al. Tumor suppressor p53 and its mutants in cancer metabolism [J]. Cancer Lett, 2015, 56: 197.
[14] Wade M, Li Y C, Wahl G M. MDM2, MDMX and p53 in oncogenesis and cancer therapy [J]. Nat Rev Cancer, 2013, 13: 83.
[15] Pei D, Zhang Y, Zheng J. Regulation of p53: a collaboration between Mdm2 and Mdmx [J]. Oncotarget, 2012, 3: 228.
[16] Mendoza M, Mandani G, and Momand J. The MDM2 gene family [J]. Biomol Concepts, 2014, 5: 9.
[17] Meng X, Franklin D A, Dong J H, et al. MDM2-p53 pathway in hepatocellular carcinoma [J]. Cancer Res, 2014, 74: 7161.
[18] Barone G, Tweddle D, Shohet J, et al. MDM2-p53 interaction in paediatric solid tumours: preclinical rationale, biomarkers and resistance [J]. Curr Drug Targets, 2014, 15: 114.
[19] Ding Q, Zhang Z M, Liu J J, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development [J]. J Med Chem, 2013, 56: 5979.
[20] Wang S, Wei S, Zhao Y J, et al. SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression [J]. Cancer Res, 2014, 74: 5855.
[21] Sun D, Li Z H, Rew Y, et al. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development [J]. J Med Chem, 2014, 57: 1454.
[22] Shangary S, Wang S. Targeting the MDM2-p53 interaction for cancer therapy [J]. Clin Cancer Res, 2008, 14: 5318.
[23] Koblish H K, Zhao S, Franks C F, et al. Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo [J]. Mol Cancer Ther, 2006, 5: 160.
[24] Lang P T, Brozell S R, Mukherjee S, et al. DOCK 6: combining techniques to model RNA-small molecule complexes [J]. RNA, 2009, 15: 1219.
[25] Trott O, Olson A J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading [J]. J Comput Chem, 2010, 31: 455.
[26] Xiao Z X, Chen J, Levine A J, et al. Interaction between the retinoblastoma protein and the oncoproteinMDM2 [J]. Nature, 1995, 375: 694.
[27] Du W, Wu J F, Walsh E M, et al. Nutlin-3 affects erxpression and function of retinoblastoma protein [J]. J Biol Chem, 2009, 284: 26315.