![conference banner](/images/conference-banner.jpeg)
摘要
癌症是世界范围内死亡的主要原因。当细胞周期调节基因由于环境和/或内部因素失去功能时,它就产生了。肿瘤抑制蛋白p53被称为基因组的守护者,在维持细胞基因组稳定性方面发挥着核心作用。超过50%的人类癌症中发现了TP53的突变,通常是由于负调控蛋白MDM2的过表达引起的。因此,通过阻断the murine double minute 2 (MDM2)与肿瘤抑制蛋白p53之间的蛋白-蛋白相互作用来重新激活p53已成为肿瘤学中最有前景的治疗策略。几种小分子已经被鉴定为有效的、选择性的和有效的p53-MDM2抑制剂。本文中,我们综述了p53-MDM2抑制剂的可给药性及其优化方法,以及按骨架类型分类的临床候选药物。
关键词: 癌症,肿瘤抑制蛋白p53,突变,p53-MDM2蛋白质相互作用,小分子抑制剂,p53重激活。
[2]
Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell, 2000, 100(1), 57-70.
[http://dx.doi.org/10.1016/S0092-8674(00)81683-9] [PMID: 10647931]
[http://dx.doi.org/10.1016/S0092-8674(00)81683-9] [PMID: 10647931]
[3]
Gupta, G.P.; Massagué, J. Cancer metastasis: building a framework. Cell, 2006, 127(4), 679-695.
[http://dx.doi.org/10.1016/j.cell.2006.11.001] [PMID: 17110329]
[http://dx.doi.org/10.1016/j.cell.2006.11.001] [PMID: 17110329]
[4]
Wang, Z.; Dabrosin, C.; Yin, X.; Fuster, M.M.; Arreola, A.; Rathmell, W.K.; Generali, D.; Nagaraju, G.P.; El-Rayes, B.; Ribatti, D.; Chen, Y.C.; Honoki, K.; Fujii, H.; Georgakilas, A.G.; Nowsheen, S.; Amedei, A.; Niccolai, E.; Amin, A.; Ashraf, S.S.; Helferich, B.; Yang, X.; Guha, G.; Bhakta, D.; Ciriolo, M.R.; Aquilano, K.; Chen, S.; Halicka, D.; Mohammed, S.I.; Azmi, A.S.; Bilsland, A.; Keith, W.N.; Jensen, L.D. Broad targeting of angiogenesis for cancer prevention and therapy. Semin. Cancer Biol., 2015, 35(Suppl.), S224-S243.
[http://dx.doi.org/10.1016/j.semcancer.2015.01.001] [PMID: 25600295]
[http://dx.doi.org/10.1016/j.semcancer.2015.01.001] [PMID: 25600295]
[5]
Martin, T.A.; Jiang, W.G. Loss of tight junction barrier function and its role in cancer metastasis. Biochim. Biophys. Acta, 2009, 1788(4), 872-891.
[http://dx.doi.org/10.1016/j.bbamem.2008.11.005] [PMID: 19059202]
[http://dx.doi.org/10.1016/j.bbamem.2008.11.005] [PMID: 19059202]
[6]
Jones, P.A.; Baylin, S.B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet., 2002, 3(6), 415-428.
[http://dx.doi.org/10.1038/nrg816] [PMID: 12042769]
[http://dx.doi.org/10.1038/nrg816] [PMID: 12042769]
[7]
Fidler, I.J.; Gersten, D.M.; Hart, I.R. The biology of cancer invasion and metastasis. Adv. Cancer Res., 1978, 28, 149-250.
[http://dx.doi.org/10.1016/S0065-230X(08)60648-X] [PMID: 360795]
[http://dx.doi.org/10.1016/S0065-230X(08)60648-X] [PMID: 360795]
[8]
Wynder, E.L.; Mushinski, M.H.; Spivak, J.C. Tobacco and alcohol consumption in relation to the development of multiple primary cancers. Cancer, 1977, 40(4)(Suppl.), 1872-1878.
[http://dx.doi.org/10.1002/1097-0142(197710)40:4+<1872:AID-CNCR2820400817>3.0.CO;2-#] [PMID: 332333]
[http://dx.doi.org/10.1002/1097-0142(197710)40:4+<1872:AID-CNCR2820400817>3.0.CO;2-#] [PMID: 332333]
[9]
Cantalupo, P.G.; Katz, J.P.; Pipas, J.M. Viral sequences in human cancer. Virology, 2018, 513, 208-216.
[http://dx.doi.org/10.1016/j.virol.2017.10.017] [PMID: 29107929]
[http://dx.doi.org/10.1016/j.virol.2017.10.017] [PMID: 29107929]
[10]
Narayanan, D.L.; Saladi, R.N.; Fox, J.L. Ultraviolet radiation and skin cancer. Int. J. Dermatol., 2010, 49(9), 978-986.
[http://dx.doi.org/10.1111/j.1365-4632.2010.04474.x] [PMID: 20883261]
[http://dx.doi.org/10.1111/j.1365-4632.2010.04474.x] [PMID: 20883261]
[11]
Yancik, R.; Ries, L.A. Aging and cancer in America. Demographic and epidemiologic perspectives. Hematol. Oncol. Clin. North Am., 2000, 14(1), 17-23.
[http://dx.doi.org/10.1016/S0889-8588(05)70275-6] [PMID: 10680069]
[http://dx.doi.org/10.1016/S0889-8588(05)70275-6] [PMID: 10680069]
[12]
Boffetta, P.; Jourenkova, N.; Gustavsson, P. Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons. Cancer Causes Control, 1997, 8(3), 444-472.
[http://dx.doi.org/10.1023/A:1018465507029] [PMID: 9498904]
[http://dx.doi.org/10.1023/A:1018465507029] [PMID: 9498904]
[13]
Anand, P.; Kunnumakkara, A.B.; Sundaram, C.; Harikumar, K.B.; Tharakan, S.T.; Lai, O.S.; Sung, B.; Aggarwal, B.B. Cancer is a preventable disease that requires major lifestyle changes. Pharm. Res., 2008, 25(9), 2097-2116.
[http://dx.doi.org/10.1007/s11095-008-9661-9] [PMID: 18626751]
[http://dx.doi.org/10.1007/s11095-008-9661-9] [PMID: 18626751]
[14]
Schafer, K.A. The cell cycle: a review. Vet. Pathol., 1998, 35(6), 461-478.
[http://dx.doi.org/10.1177/030098589803500601] [PMID: 9823588]
[http://dx.doi.org/10.1177/030098589803500601] [PMID: 9823588]
[15]
Cordon-Cardo, C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am. J. Pathol., 1995, 147(3), 545-560.
[PMID: 7677168]
[PMID: 7677168]
[16]
Kamb, A. Cell-cycle regulators and cancer. Trends Genet., 1995, 11(4), 136-140.
[http://dx.doi.org/10.1016/S0168-9525(00)89027-7] [PMID: 7732591]
[http://dx.doi.org/10.1016/S0168-9525(00)89027-7] [PMID: 7732591]
[17]
Croce, C.M. Oncogenes and cancer. N. Engl. J. Med., 2008, 358(5), 502-511.
[http://dx.doi.org/10.1056/NEJMra072367] [PMID: 18234754]
[http://dx.doi.org/10.1056/NEJMra072367] [PMID: 18234754]
[18]
Duesberg, P.H.; Stehelin, D. Oncogenes and cancer. Science, 1995, 267(5203), 1407-1408.
[http://dx.doi.org/10.1126/science.7794335] [PMID: 7794335]
[http://dx.doi.org/10.1126/science.7794335] [PMID: 7794335]
[19]
Hinds, P.W.; Weinberg, R.A. Tumor suppressor genes. Curr. Opin. Genet. Dev., 1994, 4(1), 135-141.
[http://dx.doi.org/10.1016/0959-437X(94)90102-3] [PMID: 8193533]
[http://dx.doi.org/10.1016/0959-437X(94)90102-3] [PMID: 8193533]
[20]
Wood, R.D.; Mitchell, M.; Lindahl, T. Human DNA repair genes, 2005. Mutat. Res., 2005, 577(1-2), 275-283.
[http://dx.doi.org/10.1016/j.mrfmmm.2005.03.007] [PMID: 15922366]
[http://dx.doi.org/10.1016/j.mrfmmm.2005.03.007] [PMID: 15922366]
[21]
Correia, C.; Schneider, P.A.; Dai, H.; Dogan, A.; Maurer, M.J.; Church, A.K.; Novak, A.J.; Feldman, A.L.; Wu, X.; Ding, H.; Meng, X.W.; Cerhan, J.R.; Slager, S.L.; Macon, W.R.; Habermann, T.M.; Karp, J.E.; Gore, S.D.; Kay, N.E.; Jelinek, D.F.; Witzig, T.E.; Nowakowski, G.S.; Kaufmann, S.H. BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma. Blood, 2015, 125(4), 658-667.
[http://dx.doi.org/10.1182/blood-2014-04-571786] [PMID: 25452615]
[http://dx.doi.org/10.1182/blood-2014-04-571786] [PMID: 25452615]
[22]
Park, Y.H.; Shin, H.T.; Jung, H.H.; Choi, Y.L.; Ahn, T.; Park, K.; Lee, A.; Do, I.G.; Kim, J.Y.; Ahn, J.S.; Park, W.Y.; Im, Y.H. Role of HER2 mutations in refractory metastatic breast cancers: targeted sequencing results in patients with refractory breast cancer. Oncotarget, 2015, 6(31), 32027-32038.
[http://dx.doi.org/10.18632/oncotarget.5184] [PMID: 26397225]
[http://dx.doi.org/10.18632/oncotarget.5184] [PMID: 26397225]
[23]
Xu-Monette, Z.; Deng, Q.; Manyam, G.; Tzankov, A.; Li, L.; Xia, Y.; Wang, X.X.; Zou, D.; Visco, C.; Dybkær, K.; Li, J.; Zhang, L.; Han, L.; Moreno, S.M.; Chiu, A.; Orazi, A.; Zu, Y.; Bhagat, G.; Richards, K.L.; Hsi, E.D.; Choi, W.W.L.; Krieken, J.H.; Huh, J.; Ponzoni, M.; Ferreri, A.J.M.; Parsons, B.M.; Møller, M.B.; Wang, S.A.; Miranda, R.N.; Piris, M.A.; Winter, J.N.; Medeiros, L.J.; Li, Y.; Young, K.H. MYC mutation profiling and prognostic significance in de novo diffuse large B-cell lymphoma. Clin. Cancer Res., 2016, 22(14), 3593-3605.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2296] [PMID: 26927665]
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2296] [PMID: 26927665]
[24]
Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer, 2003, 3(1), 11-22.
[http://dx.doi.org/10.1038/nrc969] [PMID: 12509763]
[http://dx.doi.org/10.1038/nrc969] [PMID: 12509763]
[25]
Chiu, I.M.; Reddy, E.P.; Givol, D.; Robbins, K.C.; Tronick, S.R.; Aaronson, S.A. Nucleotide sequence analysis identifies the human c-sis proto-oncogene as a structural gene for platelet-derived growth factor. Cell, 1984, 37(1), 123-129.
[http://dx.doi.org/10.1016/0092-8674(84)90307-6] [PMID: 6327048]
[http://dx.doi.org/10.1016/0092-8674(84)90307-6] [PMID: 6327048]
[26]
Aoki, K.; Taketo, M.M. Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene. J. Cell Sci., 2007, 120(Pt 19), 3327-3335.
[http://dx.doi.org/10.1242/jcs.03485] [PMID: 17881494]
[http://dx.doi.org/10.1242/jcs.03485] [PMID: 17881494]
[27]
Mersch, J.; Jackson, M.A.; Park, M.; Nebgen, D.; Peterson, S.K.; Singletary, C.; Arun, B.K.; Litton, J.K. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer, 2015, 121(2), 269-275.
[http://dx.doi.org/10.1002/cncr.29041] [PMID: 25224030]
[http://dx.doi.org/10.1002/cncr.29041] [PMID: 25224030]
[28]
He, X.S.; Su, Q.; Chen, Z.C.; He, X.T.; Long, Z.F.; Ling, H.; Zhang, L.R. Expression, deletion [was deleton] and mutation of p16 gene in human gastric cancer. World J. Gastroenterol., 2001, 7(4), 515-521.
[http://dx.doi.org/10.3748/wjg.v7.i4.515] [PMID: 11819820]
[http://dx.doi.org/10.3748/wjg.v7.i4.515] [PMID: 11819820]
[29]
Abbas, T.; Dutta, A. p21 in cancer: intricate networks and multiple activities. Nat. Rev. Cancer, 2009, 9(6), 400-414.
[http://dx.doi.org/10.1038/nrc2657] [PMID: 19440234]
[http://dx.doi.org/10.1038/nrc2657] [PMID: 19440234]
[30]
Muller, P.A.; Vousden, K.H. p53 mutations in cancer. Nat. Cell Biol., 2013, 15(1), 2-8.
[http://dx.doi.org/10.1038/ncb2641] [PMID: 23263379]
[http://dx.doi.org/10.1038/ncb2641] [PMID: 23263379]
[31]
de Voer, R.M.; Hahn, M.M.; Mensenkamp, A.R.; Hoischen, A.; Gilissen, C.; Henkes, A.; Spruijt, L.; van Zelst-Stams, W.A.; Kets, C.M.; Verwiel, E.T.; Nagtegaal, I.D.; Schackert, H.K.; van Kessel, A.G.; Hoogerbrugge, N.; Ligtenberg, M.J.L.; Kuiper, R.P. Deleterious germline BLM mutations and the risk for early-onset colorectal cancer. Sci. Rep., 2015, 5, 14060.
[http://dx.doi.org/10.1038/srep14060] [PMID: 26358404]
[http://dx.doi.org/10.1038/srep14060] [PMID: 26358404]
[32]
Soufir, N.; Ged, C.; Bourillon, A.; Austerlitz, F.; Chemin, C.; Stary, A.; Armier, J.; Pham, D.; Khadir, K.; Roume, J.; Hadj-Rabia, S.; Bouadjar, B.; Taieb, A.; de Verneuil, H.; Benchiki, H.; Grandchamp, B.; Sarasin, A. A prevalent mutation with founder effect in xeroderma pigmentosum group C from north Africa. J. Invest. Dermatol., 2010, 130(6), 1537-1542.
[http://dx.doi.org/10.1038/jid.2009.409] [PMID: 20054342]
[http://dx.doi.org/10.1038/jid.2009.409] [PMID: 20054342]
[33]
Chambers, A.F.; Groom, A.C.; MacDonald, I.C. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer, 2002, 2(8), 563-572.
[http://dx.doi.org/10.1038/nrc865] [PMID: 12154349]
[http://dx.doi.org/10.1038/nrc865] [PMID: 12154349]
[34]
Hall, P.A.; Meek, D.; Lane, D.P. p53--integrating the complexity. J. Pathol., 1996, 180(1), 1-5.
[http://dx.doi.org/10.1002/(SICI)1096-9896(199609)180:1<1:AID-PATH712>3.0.CO;2-U] [PMID: 8943807]
[http://dx.doi.org/10.1002/(SICI)1096-9896(199609)180:1<1:AID-PATH712>3.0.CO;2-U] [PMID: 8943807]
[35]
Lane, D.P.; Crawford, L.V. T antigen is bound to a host protein in SV40-transformed cells. Nature, 1979, 278(5701), 261-263.
[http://dx.doi.org/10.1038/278261a0] [PMID: 218111]
[http://dx.doi.org/10.1038/278261a0] [PMID: 218111]
[36]
Linzer, D.I.; Levine, A.J. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell, 1979, 17(1), 43-52.
[http://dx.doi.org/10.1016/0092-8674(79)90293-9] [PMID: 222475]
[http://dx.doi.org/10.1016/0092-8674(79)90293-9] [PMID: 222475]
[37]
Levine, A.J.; Oren, M. The first 30 years of p53: growing ever more complex. Nat. Rev. Cancer, 2009, 9(10), 749-758.
[http://dx.doi.org/10.1038/nrc2723] [PMID: 19776744]
[http://dx.doi.org/10.1038/nrc2723] [PMID: 19776744]
[38]
Koshland, D.E., Jr Molecule of the year. Science, 1993, 262(5142), 1953.
[http://dx.doi.org/10.1126/science.8266084] [PMID: 8266084]
[http://dx.doi.org/10.1126/science.8266084] [PMID: 8266084]
[39]
Joerger, A.C.; Fersht, A.R. Structural biology of the tumor suppressor p53. Annu. Rev. Biochem., 2008, 77, 557-582.
[http://dx.doi.org/10.1146/annurev.biochem.77.060806.091238] [PMID: 18410249]
[http://dx.doi.org/10.1146/annurev.biochem.77.060806.091238] [PMID: 18410249]
[40]
Lane, D.P. Cancer. p53, guardian of the genome. Nature, 1992, 358(6381), 15-16.
[http://dx.doi.org/10.1038/358015a0] [PMID: 1614522]
[http://dx.doi.org/10.1038/358015a0] [PMID: 1614522]
[41]
Vaseva, A.V.; Moll, U.M. The mitochondrial p53 pathway. Biochim. Biophys. Acta, 2009, 1787(5), 414-420.
[http://dx.doi.org/10.1016/j.bbabio.2008.10.005] [PMID: 19007744]
[http://dx.doi.org/10.1016/j.bbabio.2008.10.005] [PMID: 19007744]
[42]
Green, D.R.; Kroemer, G. Cytoplasmic functions of the tumour suppressor p53. Nature, 2009, 458(7242), 1127-1130.
[http://dx.doi.org/10.1038/nature07986] [PMID: 19407794]
[http://dx.doi.org/10.1038/nature07986] [PMID: 19407794]
[43]
Horn, H.F.; Vousden, K.H. Coping with stress: multiple ways to activate p53. Oncogene, 2007, 26(9), 1306-1316.
[http://dx.doi.org/10.1038/sj.onc.1210263] [PMID: 17322916]
[http://dx.doi.org/10.1038/sj.onc.1210263] [PMID: 17322916]
[44]
Bode, A.M.; Dong, Z. Post-translational modification of p53 in tumorigenesis. Nat. Rev. Cancer, 2004, 4(10), 793-805.
[http://dx.doi.org/10.1038/nrc1455] [PMID: 15510160]
[http://dx.doi.org/10.1038/nrc1455] [PMID: 15510160]
[45]
Vousden, K.H.; Ryan, K.M. p53 and metabolism. Nat. Rev. Cancer, 2009, 9(10), 691-700.
[http://dx.doi.org/10.1038/nrc2715] [PMID: 19759539]
[http://dx.doi.org/10.1038/nrc2715] [PMID: 19759539]
[46]
Vousden, K.H.; Lu, X. Live or let die: the cell’s response to p53. Nat. Rev. Cancer, 2002, 2(8), 594-604.
[http://dx.doi.org/10.1038/nrc864] [PMID: 12154352]
[http://dx.doi.org/10.1038/nrc864] [PMID: 12154352]
[47]
Bouaoun, L.; Sonkin, D.; Ardin, M.; Hollstein, M.; Byrnes, G.; Zavadil, J.; Olivier, M. TP53 variations in human cancers: new lessons from the IARC TP53 database and genomics data. Hum. Mutat., 2016, 37(9), 865-876.
[http://dx.doi.org/10.1002/humu.23035] [PMID: 27328919]
[http://dx.doi.org/10.1002/humu.23035] [PMID: 27328919]
[48]
Oliner, J.D.; Pietenpol, J.A.; Thiagalingam, S.; Gyuris, J.; Kinzler, K.W.; Vogelstein, B. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature, 1993, 362(6423), 857-860.
[http://dx.doi.org/10.1038/362857a0] [PMID: 8479525]
[http://dx.doi.org/10.1038/362857a0] [PMID: 8479525]
[49]
Haupt, Y.; Maya, R.; Kazaz, A.; Oren, M. Mdm2 promotes the rapid degradation of p53. Nature, 1997, 387(6630), 296-299.
[http://dx.doi.org/10.1038/387296a0] [PMID: 9153395]
[http://dx.doi.org/10.1038/387296a0] [PMID: 9153395]
[50]
Honda, R.; Tanaka, H.; Yasuda, H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett., 1997, 420(1), 25-27.
[http://dx.doi.org/10.1016/S0014-5793(97)01480-4] [PMID: 9450543]
[http://dx.doi.org/10.1016/S0014-5793(97)01480-4] [PMID: 9450543]
[51]
Varley, J.M. Germline TP53 mutations and Li-Fraumeni syndrome. Hum. Mutat., 2003, 21(3), 313-320.
[http://dx.doi.org/10.1002/humu.10185] [PMID: 12619118]
[http://dx.doi.org/10.1002/humu.10185] [PMID: 12619118]
[52]
Hainaut, P.; Hollstein, M. p53 and human cancer: the first ten thousand mutations. Adv. Cancer Res., 2000, 77, 81-137.
[http://dx.doi.org/10.1016/S0065-230X(08)60785-X] [PMID: 10549356]
[http://dx.doi.org/10.1016/S0065-230X(08)60785-X] [PMID: 10549356]
[53]
Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin., 2011, 61(2), 69-90.
[http://dx.doi.org/10.3322/caac.20107] [PMID: 21296855]
[http://dx.doi.org/10.3322/caac.20107] [PMID: 21296855]
[54]
Gasco, M.; Crook, T. The p53 network in head and neck cancer. Oral Oncol., 2003, 39(3), 222-231.
[http://dx.doi.org/10.1016/S1368-8375(02)00163-X] [PMID: 12618194]
[http://dx.doi.org/10.1016/S1368-8375(02)00163-X] [PMID: 12618194]
[55]
DeSantis, C.; Ma, J.; Bryan, L.; Jemal, A. Breast cancer statistics, 2013. CA Cancer J. Clin., 2014, 64(1), 52-62.
[http://dx.doi.org/10.3322/caac.21203] [PMID: 24114568]
[http://dx.doi.org/10.3322/caac.21203] [PMID: 24114568]
[56]
Peisch, S.F.; Van Blarigan, E.L.; Chan, J.M.; Stampfer, M.J.; Kenfield, S.A. Prostate cancer progression and mortality: a review of diet and lifestyle factors. World J. Urol., 2017, 35(6), 867-874.
[http://dx.doi.org/10.1007/s00345-016-1914-3] [PMID: 27518576]
[http://dx.doi.org/10.1007/s00345-016-1914-3] [PMID: 27518576]
[57]
Sasco, A.J.; Secretan, M.B.; Straif, K. Tobacco smoking and cancer: a brief review of recent epidemiological evidence. Lung Cancer, 2004, 45(Suppl. 2), S3-S9.
[http://dx.doi.org/10.1016/j.lungcan.2004.07.998] [PMID: 15552776]
[http://dx.doi.org/10.1016/j.lungcan.2004.07.998] [PMID: 15552776]
[58]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin., 2015, 65(1), 5-29.
[http://dx.doi.org/10.3322/caac.21254] [PMID: 25559415]
[http://dx.doi.org/10.3322/caac.21254] [PMID: 25559415]
[59]
Vogelstein, B.; Lane, D.; Levine, A.J. Surfing the p53 network. Nature, 2000, 408(6810), 307-310.
[http://dx.doi.org/10.1038/35042675] [PMID: 11099028]
[http://dx.doi.org/10.1038/35042675] [PMID: 11099028]
[60]
Michael, D.; Oren, M. The p53-Mdm2 module and the ubiquitin system. Semin. Cancer Biol., 2003, 13(1), 49-58.
[http://dx.doi.org/10.1016/S1044-579X(02)00099-8] [PMID: 12507556]
[http://dx.doi.org/10.1016/S1044-579X(02)00099-8] [PMID: 12507556]
[61]
Momand, J.; Wu, H.H.; Dasgupta, G. MDM2--master regulator of the p53 tumor suppressor protein. Gene, 2000, 242(1-2), 15-29.
[http://dx.doi.org/10.1016/S0378-1119(99)00487-4] [PMID: 10721693]
[http://dx.doi.org/10.1016/S0378-1119(99)00487-4] [PMID: 10721693]
[62]
Cahilly-Snyder, L.; Yang-Feng, T.; Francke, U.; George, D.L. Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line. Somat. Cell Mol. Genet., 1987, 13(3), 235-244.
[http://dx.doi.org/10.1007/BF01535205] [PMID: 3474784]
[http://dx.doi.org/10.1007/BF01535205] [PMID: 3474784]
[63]
Momand, J.; Zambetti, G.P.; Olson, D.C.; George, D.; Levine, A.J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell, 1992, 69(7), 1237-1245.
[http://dx.doi.org/10.1016/0092-8674(92)90644-R] [PMID: 1535557]
[http://dx.doi.org/10.1016/0092-8674(92)90644-R] [PMID: 1535557]
[64]
Shangary, S.; Wang, S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu. Rev. Pharmacol. Toxicol., 2009, 49, 223-241.
[http://dx.doi.org/10.1146/annurev.pharmtox.48.113006.094723] [PMID: 18834305]
[http://dx.doi.org/10.1146/annurev.pharmtox.48.113006.094723] [PMID: 18834305]
[65]
Kussie, P.H.; Gorina, S.; Marechal, V.; Elenbaas, B.; Moreau, J.; Levine, A.J.; Pavletich, N.P. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science, 1996, 274(5289), 948-953.
[http://dx.doi.org/10.1126/science.274.5289.948] [PMID: 8875929]
[http://dx.doi.org/10.1126/science.274.5289.948] [PMID: 8875929]
[66]
Chen, J.; Marechal, V.; Levine, A.J. Mapping of the p53 and mdm-2 interaction domains. Mol. Cell. Biol., 1993, 13(7), 4107-4114.
[http://dx.doi.org/10.1128/MCB.13.7.4107] [PMID: 7686617]
[http://dx.doi.org/10.1128/MCB.13.7.4107] [PMID: 7686617]
[67]
Vassilev, L.T.; Vu, B.T.; Graves, B.; Carvajal, D.; Podlaski, F.; Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; Fotouhi, N.; Liu, E.A. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science, 2004, 303(5659), 844-848.
[http://dx.doi.org/10.1126/science.1092472] [PMID: 14704432]
[http://dx.doi.org/10.1126/science.1092472] [PMID: 14704432]
[68]
Ag, F.H.L.R. Cis-4, 5-biaryl-2-heterocyclic imidazolines
as MDM2 inhibitors. WO2007082805, 2007.
[69]
Ag, F.H.L.R. 2,4,5-triphenyl imidazoline derivatives as
inhibitors of the in-teraction between p53 and MDM2 proteins
for use as anti-cancer agents. EP2130822A1, 2009.
[71]
Vu, B.; Wovkulich, P.; Pizzolato, G.; Lovey, A.; Ding, Q.; Jiang, N.; Liu, J.J.; Zhao, C.; Glenn, K.; Wen, Y.; Tovar, C.; Packman, K.; Vassilev, L.; Graves, B. Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development. ACS Med. Chem. Lett., 2013, 4(5), 466-469.
[http://dx.doi.org/10.1021/ml4000657] [PMID: 24900694]
[http://dx.doi.org/10.1021/ml4000657] [PMID: 24900694]
[72]
Tovar, C.; Graves, B.; Packman, K.; Filipovic, Z.; Higgins, B.; Xia, M.; Tardell, C.; Garrido, R.; Lee, E.; Kolinsky, K.; To, K.H.; Linn, M.; Podlaski, F.; Wovkulich, P.; Vu, B.; Vassilev, L.T. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res., 2013, 73(8), 2587-2597.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-2807] [PMID: 23400593]
[http://dx.doi.org/10.1158/0008-5472.CAN-12-2807] [PMID: 23400593]
[73]
Parks, D.J.; Lafrance, L.V.; Calvo, R.R.; Milkiewicz, K.L.; Gupta, V.; Lattanze, J.; Ramachandren, K.; Carver, T.E.; Petrella, E.C.; Cummings, M.D.; Maguire, D.; Grasberger, B.L.; Lu, T. 1,4-Benzodiazepine-2,5-diones as small molecule antagonists of the HDM2-p53 interaction: discovery and SAR. Bioorg. Med. Chem. Lett., 2005, 15(3), 765-770.
[http://dx.doi.org/10.1016/j.bmcl.2004.11.009] [PMID: 15664854]
[http://dx.doi.org/10.1016/j.bmcl.2004.11.009] [PMID: 15664854]
[74]
Raboisson, P.; Marugán, J.J.; Schubert, C.; Koblish, H.K.; Lu, T.; Zhao, S.; Player, M.R.; Maroney, A.C.; Reed, R.L.; Huebert, N.D.; Lattanze, J.; Parks, D.J.; Cummings, M.D. Structure-based design, synthesis, and biological evaluation of novel 1,4-diazepines as HDM2 antagonists. Bioorg. Med. Chem. Lett., 2005, 15(7), 1857-1861.
[http://dx.doi.org/10.1016/j.bmcl.2005.02.018] [PMID: 15780621]
[http://dx.doi.org/10.1016/j.bmcl.2005.02.018] [PMID: 15780621]
[75]
Pantoliano, M.W.; Petrella, E.C.; Kwasnoski, J.D.; Lobanov, V.S.; Myslik, J.; Graf, E.; Carver, T.; Asel, E.; Springer, B.A.; Lane, P.; Salemme, F.R. High-density miniaturized thermal shift assays as a general strategy for drug discovery. J. Biomol. Screen., 2001, 6(6), 429-440.
[http://dx.doi.org/10.1177/108705710100600609] [PMID: 11788061]
[http://dx.doi.org/10.1177/108705710100600609] [PMID: 11788061]
[76]
Grasberger, B.L.; Lu, T.; Schubert, C.; Parks, D.J.; Carver, T.E.; Koblish, H.K.; Cummings, M.D.; LaFrance, L.V.; Milkiewicz, K.L.; Calvo, R.R.; Maguire, D.; Lattanze, J.; Franks, C.F.; Zhao, S.; Ramachandren, K.; Bylebyl, G.R.; Zhang, M.; Manthey, C.L.; Petrella, E.C.; Pantoliano, M.W.; Deckman, I.C.; Spurlino, J.C.; Maroney, A.C.; Tomczuk, B.E.; Molloy, C.J.; Bone, R.F. Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. J. Med. Chem., 2005, 48(4), 909-912.
[http://dx.doi.org/10.1021/jm049137g] [PMID: 15715460]
[http://dx.doi.org/10.1021/jm049137g] [PMID: 15715460]
[77]
Parks, D.J.; LaFrance, L.V.; Calvo, R.R.; Milkiewicz, K.L.; Marugán, J.J.; Raboisson, P.; Schubert, C.; Koblish, H.K.; Zhao, S.; Franks, C.F.; Lattanze, J.; Carver, T.E.; Cummings, M.D.; Maguire, D.; Grasberger, B.L.; Maroney, A.C.; Lu, T. Enhanced pharmacokinetic properties of 1,4-benzodiazepine-2,5-dione antagonists of the HDM2-p53 protein-protein interaction through structure-based drug design. Bioorg. Med. Chem. Lett., 2006, 16(12), 3310-3314.
[http://dx.doi.org/10.1016/j.bmcl.2006.03.055] [PMID: 16600594]
[http://dx.doi.org/10.1016/j.bmcl.2006.03.055] [PMID: 16600594]
[78]
Marugan, J.J.; Leonard, K.; Raboisson, P.; Gushue, J.M.; Calvo, R.; Koblish, H.K.; Lattanze, J.; Zhao, S.; Cummings, M.D.; Player, M.R.; Schubert, C.; Maroney, A.C.; Lu, T. Enantiomerically pure 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists. Bioorg. Med. Chem. Lett., 2006, 16(12), 3115-3120.
[http://dx.doi.org/10.1016/j.bmcl.2006.03.067] [PMID: 16630722]
[http://dx.doi.org/10.1016/j.bmcl.2006.03.067] [PMID: 16630722]
[79]
Huang, Y.; Wolf, S.; Bista, M.; Meireles, L.; Camacho, C.; Holak, T.A.; Dömling, A. 1,4-Thienodiazepine-2,5-diones via MCR (I): synthesis, virtual space and p53-Mdm2 activity. Chem. Biol. Drug Des., 2010, 76(2), 116-129.
[http://dx.doi.org/10.1111/j.1747-0285.2010.00989.x] [PMID: 20492448]
[http://dx.doi.org/10.1111/j.1747-0285.2010.00989.x] [PMID: 20492448]
[80]
Zhuang, C.; Miao, Z.; Zhu, L.; Zhang, Y.; Guo, Z.; Yao, J.; Dong, G.; Wang, S.; Liu, Y.; Chen, H.; Sheng, C.; Zhang, W. Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the p53-MDM2 protein-protein interaction. Eur. J. Med. Chem., 2011, 46(11), 5654-5661.
[http://dx.doi.org/10.1016/j.ejmech.2011.09.043] [PMID: 21996465]
[http://dx.doi.org/10.1016/j.ejmech.2011.09.043] [PMID: 21996465]
[81]
Guo, Z.; Zhuang, C.; Zhu, L.; Zhang, Y.; Yao, J.; Dong, G.; Wang, S.; Liu, Y.; Chen, H.; Sheng, C.; Miao, Z.; Zhang, W. Structure-activity relationship and antitumor activity of thio-benzodiazepines as p53-MDM2 protein-protein interaction inhibitors. Eur. J. Med. Chem., 2012, 56, 10-16.
[http://dx.doi.org/10.1016/j.ejmech.2012.08.003] [PMID: 22940704]
[http://dx.doi.org/10.1016/j.ejmech.2012.08.003] [PMID: 22940704]
[82]
Yu, Z.; Zhuang, C.; Wu, Y.; Guo, Z.; Li, J.; Dong, G.; Yao, J.; Sheng, C.; Miao, Z.; Zhang, W. Design, synthesis and biological evaluation of sulfamide and triazole benzodiazepines as novel p53-MDM2 inhibitors. Int. J. Mol. Sci., 2014, 15(9), 15741-15753.
[http://dx.doi.org/10.3390/ijms150915741] [PMID: 25198897]
[http://dx.doi.org/10.3390/ijms150915741] [PMID: 25198897]
[83]
Zheng, Y.; Tice, C.M.; Singh, S.B. The use of spirocyclic scaffolds in drug discovery. Bioorg. Med. Chem. Lett., 2014, 24(16), 3673-3682.
[http://dx.doi.org/10.1016/j.bmcl.2014.06.081] [PMID: 25052427]
[http://dx.doi.org/10.1016/j.bmcl.2014.06.081] [PMID: 25052427]
[84]
Molvi, K.I.; Haque, N.; Awen, B.Z.; Zameeruddin, M. Synthesis of spiro compounds as medicinal agents; new opportunities for drug design and discovery. part-I: a review. World J. Pharm. Pharm. Sci., 2014, 3(12), 536-563.
[85]
Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P.P.; Tomita, Y.; Parrish, D.A.; Deschamps, J.R.; Wang, S. Structure-based design of potent non-peptide MDM2 inhibitors. J. Am. Chem. Soc., 2005, 127(29), 10130-10131.
[http://dx.doi.org/10.1021/ja051147z] [PMID: 16028899]
[http://dx.doi.org/10.1021/ja051147z] [PMID: 16028899]
[86]
Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.; Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P.P.; Wang, S. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. J. Med. Chem., 2006, 49(12), 3432-3435.
[http://dx.doi.org/10.1021/jm051122a] [PMID: 16759082]
[http://dx.doi.org/10.1021/jm051122a] [PMID: 16759082]
[87]
Ding, K.; Wang, G.P.; Deschamps, J.R.; Parrish, D.A.; Wang, S.M. Synthesis of spirooxindoles via asymmetric 1,3-dipolar cycloaddition. Tetrahedron Lett., 2005, 46(35), 5949-5951.
[http://dx.doi.org/10.1016/j.tetlet.2005.06.114]
[http://dx.doi.org/10.1016/j.tetlet.2005.06.114]
[88]
Yu, S.; Qin, D.; Shangary, S.; Chen, J.; Wang, G.; Ding, K.; McEachern, D.; Qiu, S.; Nikolovska-Coleska, Z.; Miller, R.; Kang, S.; Yang, D.; Wang, S. Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. J. Med. Chem., 2009, 52(24), 7970-7973.
[http://dx.doi.org/10.1021/jm901400z] [PMID: 19928922]
[http://dx.doi.org/10.1021/jm901400z] [PMID: 19928922]
[89]
Zhao, Y.; Yu, S.; Sun, W.; Liu, L.; Lu, J.; McEachern, D.; Shargary, S.; Bernard, D.; Li, X.; Zhao, T.; Zou, P.; Sun, D.; Wang, S. A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice. J. Med. Chem., 2013, 56(13), 5553-5561.
[http://dx.doi.org/10.1021/jm4005708] [PMID: 23786219]
[http://dx.doi.org/10.1021/jm4005708] [PMID: 23786219]
[91]
Zhang, Z.; Ding, Q.; Liu, J.J.; Zhang, J.; Jiang, N.; Chu, X.J.; Bartkovitz, D.; Luk, K.C.; Janson, C.; Tovar, C.; Filipovic, Z.M.; Higgins, B.; Glenn, K.; Packman, K.; Vassilev, L.T.; Graves, B. Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy. Bioorg. Med. Chem., 2014, 22(15), 4001-4009.
[http://dx.doi.org/10.1016/j.bmc.2014.05.072] [PMID: 24997575]
[http://dx.doi.org/10.1016/j.bmc.2014.05.072] [PMID: 24997575]
[92]
Shu, L.H.; Li, Z.Z.; Gu, C.; Fishlock, D. Synthesis of a spiroindolinone pyrrolidinecarboxamide MDM2 antagonist. Org. Process Res. Dev., 2013, 17(2), 247-256.
[http://dx.doi.org/10.1021/op3003213]
[http://dx.doi.org/10.1021/op3003213]
[93]
Zhang, Z.; Chu, X.J.; Liu, J.J.; Ding, Q.; Zhang, J.; Bartkovitz, D.; Jiang, N.; Karnachi, P.; So, S.S.; Tovar, C.; Filipovic, Z.M.; Higgins, B.; Glenn, K.; Packman, K.; Vassilev, L.; Graves, B. Discovery of potent and orally active p53-MDM2 inhibitors RO5353 and RO2468 for potential clinical development. ACS Med. Chem. Lett., 2013, 5(2), 124-127.
[http://dx.doi.org/10.1021/ml400359z] [PMID: 24900784]
[http://dx.doi.org/10.1021/ml400359z] [PMID: 24900784]
[94]
Ribeiro, C.J.A.; Amaral, J.D.; Rodrigues, C.M.P.; Moreira, R.; Santos, M.M. Synthesis and evaluation of spiroisoxazoline oxindoles as anticancer agents. Bioorg. Med. Chem., 2014, 22(1), 577-584.
[http://dx.doi.org/10.1016/j.bmc.2013.10.048] [PMID: 24268795]
[http://dx.doi.org/10.1016/j.bmc.2013.10.048] [PMID: 24268795]
[95]
Aguilar, A.; Sun, W.; Liu, L.; Lu, J.; McEachern, D.; Bernard, D.; Deschamps, J.R.; Wang, S. Design of chemically stable, potent, and efficacious MDM2 inhibitors that exploit the retro-mannich ring-opening-cyclization reaction mechanism in spiro-oxindoles. J. Med. Chem., 2014, 57(24), 10486-10498.
[http://dx.doi.org/10.1021/jm501541j] [PMID: 25496041]
[http://dx.doi.org/10.1021/jm501541j] [PMID: 25496041]
[96]
Kumar, A.; Gupta, G.; Bishnoi, A.K.; Saxena, R.; Saini, K.S.; Konwar, R.; Kumar, S.; Dwivedi, A. Design and synthesis of new bioisosteres of spirooxindoles (MI-63/219) as anti-breast cancer agents. Bioorg. Med. Chem., 2015, 23(4), 839-848.
[http://dx.doi.org/10.1016/j.bmc.2014.12.037] [PMID: 25618595]
[http://dx.doi.org/10.1016/j.bmc.2014.12.037] [PMID: 25618595]
[97]
Zhang, L.; Ren, W.; Wang, X.; Zhang, J.; Liu, J.; Zhao, L.; Zhang, X. Discovery of novel polycyclic spiro-fused carbocyclicoxindole-based anticancer agents. Eur. J. Med. Chem., 2017, 126, 1071-1082.
[http://dx.doi.org/10.1016/j.ejmech.2016.12.021] [PMID: 28027532]
[http://dx.doi.org/10.1016/j.ejmech.2016.12.021] [PMID: 28027532]
[98]
Wang, S.; Jiang, Y.; Wu, S.; Dong, G.; Miao, Z.; Zhang, W.; Sheng, C. Meeting organocatalysis with drug discovery: asymmetric synthesis of 3,3′-spirooxindoles fused with tetrahydrothiopyrans as novel p53-MDM2 inhibitors. Org. Lett., 2016, 18(5), 1028-1031.
[http://dx.doi.org/10.1021/acs.orglett.6b00155] [PMID: 26883465]
[http://dx.doi.org/10.1021/acs.orglett.6b00155] [PMID: 26883465]
[99]
Ji, C.; Wang, S.; Chen, S.; He, S.; Jiang, Y.; Miao, Z.; Li, J.; Sheng, C. Design, synthesis and biological evaluation of novel antitumor spirotetrahydrothiopyran-oxindole derivatives as potent p53-MDM2 inhibitors. Bioorg. Med. Chem., 2017, 25(20), 5268-5277.
[http://dx.doi.org/10.1016/j.bmc.2017.07.049] [PMID: 28797774]
[http://dx.doi.org/10.1016/j.bmc.2017.07.049] [PMID: 28797774]
[100]
Narasimhan, B.; Sharma, D.; Kumar, P. Biological importance of imidazole nucleus in the new millennium. Med. Chem. Res., 2011, 20(8), 1119-1140.
[http://dx.doi.org/10.1007/s00044-010-9472-5]
[http://dx.doi.org/10.1007/s00044-010-9472-5]
[101]
Yerragunta, V.; Suman, D.; Swamy, K.; Anusha, V.; Patil, P.; Naresh, M. Pyrazole and its biological activity. Pharma. Tutor, 2014, 2(1), 40-48.
[102]
Mishra, R.; Sharma, P.K. A review on synthesis and medicinal importance of thiophene. Int. J. Eng. Appl. Sci., 2015, 1(1), 46-59.
[103]
Wang, W.; Zhu, X.; Hong, X.; Zheng, L.; Zhu, H.; Hu, Y. Identification of novel inhibitors of p53-MDM2 interaction facilitated by pharmacophore-based virtual screening combining molecular docking strategy. Med.Chem.Comm, 2013, 4(2), 411-416.
[http://dx.doi.org/10.1039/c2md20208e]
[http://dx.doi.org/10.1039/c2md20208e]
[104]
Wang, W.; Shangguan, S.; Qiu, N.; Hu, C.; Zhang, L.; Hu, Y. Design, synthesis and biological evaluation of novel 3,4,5-trisubstituted aminothiophenes as inhibitors of p53-MDM2 interaction. Part 1. Bioorg. Med. Chem., 2013, 21(11), 2879-2885.
[http://dx.doi.org/10.1016/j.bmc.2013.03.061] [PMID: 23601819]
[http://dx.doi.org/10.1016/j.bmc.2013.03.061] [PMID: 23601819]
[105]
Wang, W.; Lv, D.; Qiu, N.; Zhang, L.; Hu, C.; Hu, Y. Design, synthesis and biological evaluation of novel 3,4,5-trisubstituted aminothiophenes as inhibitors of p53-MDM2 interaction. Part 2. Bioorg. Med. Chem., 2013, 21(11), 2886-2894.
[http://dx.doi.org/10.1016/j.bmc.2013.03.070] [PMID: 23611770]
[http://dx.doi.org/10.1016/j.bmc.2013.03.070] [PMID: 23611770]
[106]
Gomha, S.M.; Eldebss, T.M.; Abdulla, M.M.; Mayhoub, A.S. Diphenylpyrroles: Novel p53 activators. Eur. J. Med. Chem., 2014, 82, 472-479.
[http://dx.doi.org/10.1016/j.ejmech.2014.05.082] [PMID: 24934571]
[http://dx.doi.org/10.1016/j.ejmech.2014.05.082] [PMID: 24934571]
[107]
Popowicz, G.M.; Czarna, A.; Wolf, S.; Wang, K.; Wang, W.; Dömling, A.; Holak, T.A. Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery. Cell Cycle, 2010, 9(6), 1104-1111.
[http://dx.doi.org/10.4161/cc.9.6.10956] [PMID: 20237429]
[http://dx.doi.org/10.4161/cc.9.6.10956] [PMID: 20237429]
[108]
Furet, P.; Chène, P.; De Pover, A.; Valat, T.S.; Lisztwan, J.H.; Kallen, J.; Masuya, K. The central valine concept provides an entry in a new class of non peptide inhibitors of the p53-MDM2 interaction. Bioorg. Med. Chem. Lett., 2012, 22(10), 3498-3502.
[http://dx.doi.org/10.1016/j.bmcl.2012.03.083] [PMID: 22507962]
[http://dx.doi.org/10.1016/j.bmcl.2012.03.083] [PMID: 22507962]
[109]
Vaupel, A.; Bold, G.; De Pover, A.; Stachyra-Valat, T.; Lisztwan, J.H.; Kallen, J.; Masuya, K.; Furet, P. Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction. Bioorg. Med. Chem. Lett., 2014, 24(9), 2110-2114.
[http://dx.doi.org/10.1016/j.bmcl.2014.03.039] [PMID: 24704029]
[http://dx.doi.org/10.1016/j.bmcl.2014.03.039] [PMID: 24704029]
[110]
Hu, C.; Gao, Y.; Du, W. Design, synthesis, and biological evaluation of pyrazole derivatives. Chem. Biol. Drug Des., 2016, 87(5), 673-679.
[http://dx.doi.org/10.1111/cbdd.12699] [PMID: 26648479]
[http://dx.doi.org/10.1111/cbdd.12699] [PMID: 26648479]
[111]
Surmiak, E.; Neochoritis, C.G.; Musielak, B.; Twarda-Clapa, A.; Kurpiewska, K.; Dubin, G.; Camacho, C.; Holak, T.A.; Dömling, A. Rational design and synthesis of 1,5-disubstituted tetrazoles as potent inhibitors of the MDM2-p53 interaction. Eur. J. Med. Chem., 2017, 126, 384-407.
[http://dx.doi.org/10.1016/j.ejmech.2016.11.029] [PMID: 27907876]
[http://dx.doi.org/10.1016/j.ejmech.2016.11.029] [PMID: 27907876]
[112]
Zhuang, C.; Miao, Z.; Zhu, L.; Dong, G.; Guo, Z.; Wang, S.; Zhang, Y.; Wu, Y.; Yao, J.; Sheng, C.; Zhang, W. Discovery, synthesis, and biological evaluation of orally active pyrrolidone derivatives as novel inhibitors of p53-MDM2 protein-protein interaction. J. Med. Chem., 2012, 55(22), 9630-9642.
[http://dx.doi.org/10.1021/jm300969t] [PMID: 23046248]
[http://dx.doi.org/10.1021/jm300969t] [PMID: 23046248]
[113]
Li, J.; Wu, Y.; Guo, Z.; Zhuang, C.; Yao, J.; Dong, G.; Yu, Z.; Min, X.; Wang, S.; Liu, Y.; Wu, S.; Zhu, S.; Sheng, C.; Miao, Z.; Zhang, W. Discovery of 1-arylpyrrolidone derivatives as potent p53-MDM2 inhibitors based on molecule fusing strategy. Bioorg. Med. Chem. Lett., 2014, 24(12), 2648-2650.
[http://dx.doi.org/10.1016/j.bmcl.2014.04.063] [PMID: 24813735]
[http://dx.doi.org/10.1016/j.bmcl.2014.04.063] [PMID: 24813735]
[114]
Surmiak, E.; Twarda-Clapa, A.; Zak, K.M.; Musielak, B.; Tomala, M.D.; Kubica, K.; Grudnik, P.; Madej, M.; Jablonski, M.; Potempa, J.; Kalinowska-Tluscik, J.; Dömling, A.; Dubin, G.; Holak, T.A. Unique mdm2-binding mode of the 3-pyrrolin-2-one- and 2-furanone-based antagonists of the p53-MDM2 interaction. ACS Chem. Biol., 2016, 11(12), 3310-3318.
[http://dx.doi.org/10.1021/acschembio.6b00596] [PMID: 27709883]
[http://dx.doi.org/10.1021/acschembio.6b00596] [PMID: 27709883]
[115]
Sharma, V.; Chitranshi, N.; Agarwal, A.K. Significance and biological importance of pyrimidine in the microbial world. Int. J. Med. Chem., 2014, 2014 202784
[http://dx.doi.org/10.1155/2014/202784] [PMID: 25383216]
[http://dx.doi.org/10.1155/2014/202784] [PMID: 25383216]
[116]
Ma, Y.; Lahue, B.R.; Gibeau, C.R.; Shipps, G.W., Jr; Bogen, S.L.; Wang, Y.; Guo, Z.; Guzi, T.J. Pivotal role of an aliphatic side chain in the development of an HDM2 inhibitor. ACS Med. Chem. Lett., 2014, 5(5), 572-575.
[http://dx.doi.org/10.1021/ml500019s] [PMID: 24900882]
[http://dx.doi.org/10.1021/ml500019s] [PMID: 24900882]
[117]
Bogen, S.L.; Pan, W.; Gibeau, C.R.; Lahue, B.R.; Ma, Y.; Nair, L.G.; Seigel, E.; Shipps, G.W., Jr; Tian, Y.; Wang, Y.; Lin, Y.; Liu, M.; Liu, S.; Mirza, A.; Wang, X.; Lipari, P.; Seidel-Dugan, C.; Hicklin, D.J.; Bishop, W.R.; Rindgen, D.; Nomeir, A.; Prosise, W.; Reichert, P.; Scapin, G.; Strickland, C.; Doll, R.J. Discovery of novel 3,3-disubstituted piperidines as orally bioavailable, potent, and efficacious HDM2-p53 inhibitors. ACS Med. Chem. Lett., 2016, 7(3), 324-329.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00472] [PMID: 26985323]
[http://dx.doi.org/10.1021/acsmedchemlett.5b00472] [PMID: 26985323]
[118]
Tian, Y.; Ma, Y.; Gibeau, C.R.; Lahue, B.R.; Shipps, G.W., Jr; Strickland, C.; Bogen, S.L. Structure-activity relationship study of 4-substituted piperidines at Leu26 moiety of novel p53-hDM2 inhibitors. Bioorg. Med. Chem. Lett., 2016, 26(11), 2735-2738.
[http://dx.doi.org/10.1016/j.bmcl.2016.03.078] [PMID: 27080185]
[http://dx.doi.org/10.1016/j.bmcl.2016.03.078] [PMID: 27080185]
[119]
Rew, Y.; Sun, D.; Gonzalez-Lopez De Turiso, F.; Bartberger, M.D.; Beck, H.P.; Canon, J.; Chen, A.; Chow, D.; Deignan, J.; Fox, B.M.; Gustin, D.; Huang, X.; Jiang, M.; Jiao, X.; Jin, L.; Kayser, F.; Kopecky, D.J.; Li, Y.; Lo, M.C.; Long, A.M.; Michelsen, K.; Oliner, J.D.; Osgood, T.; Ragains, M.; Saiki, A.Y.; Schneider, S.; Toteva, M.; Yakowec, P.; Yan, X.; Ye, Q.; Yu, D.; Zhao, X.; Zhou, J.; Medina, J.C.; Olson, S.H. Structure-based design of novel inhibitors of the MDM2-p53 interaction. J. Med. Chem., 2012, 55(11), 4936-4954.
[http://dx.doi.org/10.1021/jm300354j] [PMID: 22524527]
[http://dx.doi.org/10.1021/jm300354j] [PMID: 22524527]
[120]
Bernard, D.; Zhao, Y.; Wang, S. AM-8553: a novel MDM2 inhibitor with a promising outlook for potential clinical development. J. Med. Chem., 2012, 55(11), 4934-4935.
[http://dx.doi.org/10.1021/jm3007068] [PMID: 22624960]
[http://dx.doi.org/10.1021/jm3007068] [PMID: 22624960]
[121]
Sun, D.; Li, Z.; Rew, Y.; Gribble, M.; Bartberger, M.D.; Beck, H.P.; Canon, J.; Chen, A.; Chen, X.; Chow, D.; Deignan, J.; Duquette, J.; Eksterowicz, J.; Fisher, B.; Fox, B.M.; Fu, J.; Gonzalez, A.Z.; Gonzalez-Lopez De Turiso, F.; Houze, J.B.; Huang, X.; Jiang, M.; Jin, L.; Kayser, F.; Liu, J.J.; Lo, M.C.; Long, A.M.; Lucas, B.; McGee, L.R.; McIntosh, J.; Mihalic, J.; Oliner, J.D.; Osgood, T.; Peterson, M.L.; Roveto, P.; Saiki, A.Y.; Shaffer, P.; Toteva, M.; Wang, Y.; Wang, Y.C.; Wortman, S.; Yakowec, P.; Yan, X.; Ye, Q.; Yu, D.; Yu, M.; Zhao, X.; Zhou, J.; Zhu, J.; Olson, S.H.; Medina, J.C. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J. Med. Chem., 2014, 57(4), 1454-1472.
[http://dx.doi.org/10.1021/jm401753e] [PMID: 24456472]
[http://dx.doi.org/10.1021/jm401753e] [PMID: 24456472]
[122]
Gonzalez, A.Z.; Li, Z.; Beck, H.P.; Canon, J.; Chen, A.; Chow, D.; Duquette, J.; Eksterowicz, J.; Fox, B.M.; Fu, J.; Huang, X.; Houze, J.; Jin, L.; Li, Y.; Ling, Y.; Lo, M.C.; Long, A.M.; McGee, L.R.; McIntosh, J.; Oliner, J.D.; Osgood, T.; Rew, Y.; Saiki, A.Y.; Shaffer, P.; Wortman, S.; Yakowec, P.; Yan, X.; Ye, Q.; Yu, D.; Zhao, X.; Zhou, J.; Olson, S.H.; Sun, D.; Medina, J.C. Novel inhibitors of the MDM2-p53 interaction featuring hydrogen bond acceptors as carboxylic acid isosteres. J. Med. Chem., 2014, 57(7), 2963-2988.
[http://dx.doi.org/10.1021/jm401911v] [PMID: 24601644]
[http://dx.doi.org/10.1021/jm401911v] [PMID: 24601644]
[123]
Rew, Y.; Sun, D.; Yan, X.; Beck, H.P.; Canon, J.; Chen, A.; Duquette, J.; Eksterowicz, J.; Fox, B.M.; Fu, J.; Gonzalez, A.Z.; Houze, J.; Huang, X.; Jiang, M.; Jin, L.; Li, Y.; Li, Z.; Ling, Y.; Lo, M.C.; Long, A.M.; McGee, L.R.; McIntosh, J.; Oliner, J.D.; Osgood, T.; Saiki, A.Y.; Shaffer, P.; Wang, Y.C.; Wortman, S.; Yakowec, P.; Ye, Q.; Yu, D.; Zhao, X.; Zhou, J.; Medina, J.C.; Olson, S.H. Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction. J. Med. Chem., 2014, 57(24), 10499-10511.
[http://dx.doi.org/10.1021/jm501550p] [PMID: 25384157]
[http://dx.doi.org/10.1021/jm501550p] [PMID: 25384157]
[124]
Gonzalez-Lopez de Turiso, F.; Sun, D.; Rew, Y.; Bartberger, M.D.; Beck, H.P.; Canon, J.; Chen, A.; Chow, D.; Correll, T.L.; Huang, X.; Julian, L.D.; Kayser, F.; Lo, M.C.; Long, A.M.; McMinn, D.; Oliner, J.D.; Osgood, T.; Powers, J.P.; Saiki, A.Y.; Schneider, S.; Shaffer, P.; Xiao, S.H.; Yakowec, P.; Yan, X.; Ye, Q.; Yu, D.; Zhao, X.; Zhou, J.; Medina, J.C.; Olson, S.H. Rational design and binding mode duality of MDM2-p53 inhibitors. J. Med. Chem., 2013, 56(10), 4053-4070.
[http://dx.doi.org/10.1021/jm400293z] [PMID: 23597064]
[http://dx.doi.org/10.1021/jm400293z] [PMID: 23597064]
[125]
Pettersson, M.; Quant, M.; Min, J.; Iconaru, L.; Kriwacki, R.W.; Waddell, M.B.; Guy, R.K.; Luthman, K.; Grøtli, M. Design, synthesis and evaluation of 2,5-diketopiperazines as inhibitors of the MDM2-p53 interaction. PLoS One, 2015, 10(10)e0137867
[http://dx.doi.org/10.1371/journal.pone.0137867] [PMID: 26427060]
[http://dx.doi.org/10.1371/journal.pone.0137867] [PMID: 26427060]
[126]
Bansal, Y.; Silakari, O. The therapeutic journey of benzimidazoles: a review. Bioorg. Med. Chem., 2012, 20(21), 6208-6236.
[http://dx.doi.org/10.1016/j.bmc.2012.09.013] [PMID: 23031649]
[http://dx.doi.org/10.1016/j.bmc.2012.09.013] [PMID: 23031649]
[127]
Fascio, M.L.; Errea, M.I.; D’Accorso, N.B. Imidazothiazole and related heterocyclic systems. Synthesis, chemical and biological properties. Eur. J. Med. Chem., 2015, 90, 666-683.
[http://dx.doi.org/10.1016/j.ejmech.2014.12.012] [PMID: 25499987]
[http://dx.doi.org/10.1016/j.ejmech.2014.12.012] [PMID: 25499987]
[128]
Sharma, V.; Kumar, P.; Pathak, D. Biological importance of the indole nucleus in recent years: a comprehensive review. J. Heterocycl. Chem., 2010, 47(3), 491-502.
[http://dx.doi.org/10.1002/jhet.349]
[http://dx.doi.org/10.1002/jhet.349]
[129]
Maiti, M.; Kumar, G.S. Polymorphic nucleic acid binding of bioactive isoquinoline alkaloids and their role in cancer. J. Nucleic Acids, 2010, 2010 593408
[http://dx.doi.org/10.4061/2010/593408] [PMID: 20814427]
[http://dx.doi.org/10.4061/2010/593408] [PMID: 20814427]
[130]
Kaur, K.; Jain, M.; Reddy, R.P.; Jain, R. Quinolines and structurally related heterocycles as antimalarials. Eur. J. Med. Chem., 2010, 45(8), 3245-3264.
[http://dx.doi.org/10.1016/j.ejmech.2010.04.011] [PMID: 20466465]
[http://dx.doi.org/10.1016/j.ejmech.2010.04.011] [PMID: 20466465]
[131]
Miyazaki, M.; Kawato, H.; Naito, H.; Ikeda, M.; Miyazaki, M.; Kitagawa, M.; Seki, T.; Fukutake, S.; Aonuma, M.; Soga, T. Discovery of novel dihydroimidazothiazole derivatives as p53-MDM2 protein-protein interaction inhibitors: synthesis, biological evaluation and structure-activity relationships. Bioorg. Med. Chem. Lett., 2012, 22(20), 6338-6342.
[http://dx.doi.org/10.1016/j.bmcl.2012.08.086] [PMID: 22995624]
[http://dx.doi.org/10.1016/j.bmcl.2012.08.086] [PMID: 22995624]
[132]
Miyazaki, M.; Naito, H.; Sugimoto, Y.; Kawato, H.; Okayama, T.; Shimizu, H.; Miyazaki, M.; Kitagawa, M.; Seki, T.; Fukutake, S.; Aonuma, M.; Soga, T. Lead optimization of novel p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Bioorg. Med. Chem. Lett., 2013, 23(3), 728-732.
[http://dx.doi.org/10.1016/j.bmcl.2012.11.091] [PMID: 23266121]
[http://dx.doi.org/10.1016/j.bmcl.2012.11.091] [PMID: 23266121]
[133]
Miyazaki, M.; Naito, H.; Sugimoto, Y.; Yoshida, K.; Kawato, H.; Okayama, T.; Shimizu, H.; Miyazaki, M.; Kitagawa, M.; Seki, T.; Fukutake, S.; Shiose, Y.; Aonuma, M.; Soga, T. Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors. Bioorg. Med. Chem., 2013, 21(14), 4319-4331.
[http://dx.doi.org/10.1016/j.bmc.2013.04.056] [PMID: 23685175]
[http://dx.doi.org/10.1016/j.bmc.2013.04.056] [PMID: 23685175]
[134]
Miyazaki, M.; Uoto, K.; Sugimoto, Y.; Naito, H.; Yoshida, K.; Okayama, T.; Kawato, H.; Miyazaki, M.; Kitagawa, M.; Seki, T.; Fukutake, S.; Aonuma, M.; Soga, T. Discovery of DS-5272 as a promising candidate: A potent and orally active p53-MDM2 interaction inhibitor. Bioorg. Med. Chem., 2015, 23(10), 2360-2367.
[http://dx.doi.org/10.1016/j.bmc.2015.03.069] [PMID: 25882531]
[http://dx.doi.org/10.1016/j.bmc.2015.03.069] [PMID: 25882531]
[135]
Furet, P.; Masuya, K.; Kallen, J.; Stachyra-Valat, T.; Ruetz, S.; Guagnano, V.; Holzer, P.; Mah, R.; Stutz, S.; Vaupel, A.; Chène, P.; Jeay, S.; Schlapbach, A. Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument. Bioorg. Med. Chem. Lett., 2016, 26(19), 4837-4841.
[http://dx.doi.org/10.1016/j.bmcl.2016.08.010] [PMID: 27542305]
[http://dx.doi.org/10.1016/j.bmcl.2016.08.010] [PMID: 27542305]
[136]
Zhuang, C.; Miao, Z.; Wu, Y.; Guo, Z.; Li, J.; Yao, J.; Xing, C.; Sheng, C.; Zhang, W. Double-edged swords as cancer therapeutics: novel, orally active, small molecules simultaneously inhibit p53-MDM2 interaction and the NF-κB pathway. J. Med. Chem., 2014, 57(3), 567-577.
[http://dx.doi.org/10.1021/jm401800k] [PMID: 24428757]
[http://dx.doi.org/10.1021/jm401800k] [PMID: 24428757]
[137]
Zhou, W.H.; Xu, X.G.; Li, J.; Min, X.; Yao, J.Z.; Dong, G.Q.; Zhuang, C.L.; Miao, Z.Y.; Zhang, W.N. Design, synthesis and structure-activity relationship of 4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-ones as potent p53-MDM2 inhibitors. Chin. Chem. Lett., 2017, 28(2), 422-425.
[http://dx.doi.org/10.1016/j.cclet.2016.09.001]
[http://dx.doi.org/10.1016/j.cclet.2016.09.001]
[138]
Soares, J.; Pereira, N.A.; Monteiro, Â.; Leão, M.; Bessa, C.; Dos Santos, D.J.; Raimundo, L.; Queiroz, G.; Bisio, A.; Inga, A.; Pereira, C.; Santos, M.M.M.; Saraiva, L. Oxazoloisoindolinones with in vitro antitumor activity selectively activate a p53-pathway through potential inhibition of the p53-MDM2 interaction. Eur. J. Pharm. Sci., 2015, 66, 138-147.
[http://dx.doi.org/10.1016/j.ejps.2014.10.006] [PMID: 25312347]
[http://dx.doi.org/10.1016/j.ejps.2014.10.006] [PMID: 25312347]
[139]
Rezk, M.S.; Abdel-Halim, M.; Keeton, A.; Franklin, D.; Bauer, M.; Boeckler, F.M.; Engel, M.; Hartmann, R.W.; Zhang, Y.; Piazza, G.A.; Abadi, A.H. Synthesis and optimization of new 3,6-disubstitutedindole derivatives and their evaluation as anticancer agents targeting the MDM2/MDMX complex. Chem. Pharm. Bull. (Tokyo), 2016, 64(1), 34-41.
[http://dx.doi.org/10.1248/cpb.c15-00608] [PMID: 26726742]
[http://dx.doi.org/10.1248/cpb.c15-00608] [PMID: 26726742]
[140]
Wu, L.T.; Jiang, Z.; Shen, J.J.; Yi, H.; Zhan, Y.C.; Sha, M.Q.; Wang, Z.; Xue, S.T.; Li, Z.R. Design, synthesis and biological evaluation of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives as antitumour agents. Eur. J. Med. Chem., 2016, 114, 328-336.
[http://dx.doi.org/10.1016/j.ejmech.2016.03.029] [PMID: 27017265]
[http://dx.doi.org/10.1016/j.ejmech.2016.03.029] [PMID: 27017265]
[141]
Zheng, G.H.; Shen, J.J.; Zhan, Y.C.; Yi, H.; Xue, S.T.; Wang, Z.; Ji, X.Y.; Li, Z.R. Design, synthesis and in vitro and in vivo antitumour activity of 3-benzylideneindolin-2-one derivatives, a novel class of small-molecule inhibitors of the MDM2-p53 interaction. Eur. J. Med. Chem., 2014, 81, 277-288.
[http://dx.doi.org/10.1016/j.ejmech.2014.05.027] [PMID: 24852275]
[http://dx.doi.org/10.1016/j.ejmech.2014.05.027] [PMID: 24852275]
[142]
Wang, W.; Cao, H.; Wolf, S.; Camacho-Horvitz, M.S.; Holak, T.A.; Dömling, A. Benzimidazole-2-one: a novel anchoring principle for antagonizing p53-Mdm2. Bioorg. Med. Chem., 2013, 21(14), 3982-3995.
[http://dx.doi.org/10.1016/j.bmc.2012.06.020] [PMID: 22789708]
[http://dx.doi.org/10.1016/j.bmc.2012.06.020] [PMID: 22789708]
[143]
Hardcastle, I.R.; Ahmed, S.U.; Atkins, H.; Calvert, A.H.; Curtin, N.J.; Farnie, G.; Golding, B.T.; Griffin, R.J.; Guyenne, S.; Hutton, C.; Källblad, P.; Kemp, S.J.; Kitching, M.S.; Newell, D.R.; Norbedo, S.; Northen, J.S.; Reid, R.J.; Saravanan, K.; Willems, H.M.G.; Lunec, J. Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction. Bioorg. Med. Chem. Lett., 2005, 15(5), 1515-1520.
[http://dx.doi.org/10.1016/j.bmcl.2004.12.061] [PMID: 15713419]
[http://dx.doi.org/10.1016/j.bmcl.2004.12.061] [PMID: 15713419]
[144]
Hardcastle, I.R.; Liu, J.; Valeur, E.; Watson, A.; Ahmed, S.U.; Blackburn, T.J.; Bennaceur, K.; Clegg, W.; Drummond, C.; Endicott, J.A.; Golding, B.T.; Griffin, R.J.; Gruber, J.; Haggerty, K.; Harrington, R.W.; Hutton, C.; Kemp, S.; Lu, X.; McDonnell, J.M.; Newell, D.R.; Noble, M.E.M.; Payne, S.L.; Revill, C.H.; Riedinger, C.; Xu, Q.; Lunec, J. Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein-protein interaction: structure-activity studies leading to improved potency. J. Med. Chem., 2011, 54(5), 1233-1243.
[http://dx.doi.org/10.1021/jm1011929] [PMID: 21314128]
[http://dx.doi.org/10.1021/jm1011929] [PMID: 21314128]
[145]
Watson, A.F.; Liu, J.; Bennaceur, K.; Drummond, C.J.; Endicott, J.A.; Golding, B.T.; Griffin, R.J.; Haggerty, K.; Lu, X.; McDonnell, J.M.; Newell, D.R.; Noble, M.E.M.; Revill, C.H.; Riedinger, C.; Xu, Q.; Zhao, Y.; Lunec, J.; Hardcastle, I.R. MDM2-p53 protein-protein interaction inhibitors: a-ring substituted isoindolinones. Bioorg. Med. Chem. Lett., 2011, 21(19), 5916-5919.
[http://dx.doi.org/10.1016/j.bmcl.2011.07.084] [PMID: 21875801]
[http://dx.doi.org/10.1016/j.bmcl.2011.07.084] [PMID: 21875801]
[146]
Neochoritis, C.G.; Wang, K.; Estrada-Ortiz, N.; Herdtweck, E.; Kubica, K.; Twarda, A.; Zak, K.M.; Holak, T.A.; Dömling, A. 2,30-Bis(10H-indole) heterocycles: New p53/MDM2/MDMX antagonists. Bioorg. Med. Chem. Lett., 2015, 25(24), 5661-5666.
[http://dx.doi.org/10.1016/j.bmcl.2015.11.019] [PMID: 26584879]
[http://dx.doi.org/10.1016/j.bmcl.2015.11.019] [PMID: 26584879]
[147]
Gessier, F.; Kallen, J.; Jacoby, E.; Chène, P.; Stachyra-Valat, T.; Ruetz, S.; Jeay, S.; Holzer, P.; Masuya, K.; Furet, P. Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode. Bioorg. Med. Chem. Lett., 2015, 25(17), 3621-3625.
[http://dx.doi.org/10.1016/j.bmcl.2015.06.058] [PMID: 26141769]
[http://dx.doi.org/10.1016/j.bmcl.2015.06.058] [PMID: 26141769]
[148]
Holzer, P.; Masuya, K.; Furet, P.; Kallen, J.; Valat-Stachyra, T.; Ferretti, S.; Berghausen, J.; Bouisset-Leonard, M.; Buschmann, N.; Pissot-Soldermann, C.; Rynn, C.; Ruetz, S.; Stutz, S.; Chène, P.; Jeay, S.; Gessier, F. Discovery of a dihydroisoquinolinone derivative (NVP-CGM097) a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors. J. Med. Chem., 2015, 58(16), 6348-6358.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00810] [PMID: 26181851]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00810] [PMID: 26181851]
[149]
Punganuru, S.R.; Madala, H.R.; Venugopal, S.N.; Samala, R.; Mikelis, C.; Srivenugopal, K.S. Design and synthesis of a C7-aryl piperlongumine derivative with potent antimicrotubule and mutant p53-reactivating properties. Eur. J. Med. Chem., 2016, 107, 233-244.
[http://dx.doi.org/10.1016/j.ejmech.2015.10.052] [PMID: 26599530]
[http://dx.doi.org/10.1016/j.ejmech.2015.10.052] [PMID: 26599530]
[150]
Pereira, D.; Lima, R.T.; Palmeira, A.; Seca, H.; Soares, J.; Gomes, S.; Raimundo, L.; Maciel, C.; Pinto, M.; Sousa, E.; Vasconcelos, M.H.; Saraiva, L.; Cidade, H. Design and synthesis of new inhibitors of p53-MDM2 interaction with a chalcone scaffold. Arab. J. Chem., 2016.
[http://dx.doi.org/10.1016/j.arabjc.2016.04.015]
[http://dx.doi.org/10.1016/j.arabjc.2016.04.015]
[151]
Beck, H.P.; DeGraffenreid, M.; Fox, B.; Allen, J.G.; Rew, Y.; Schneider, S.; Saiki, A.Y.; Yu, D.; Oliner, J.D.; Salyers, K.; Ye, Q.; Olson, S. Improvement of the synthesis and pharmacokinetic properties of chromenotriazolopyrimidine MDM2-p53 protein-protein inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(9), 2752-2755.
[http://dx.doi.org/10.1016/j.bmcl.2010.11.027] [PMID: 21123063]
[http://dx.doi.org/10.1016/j.bmcl.2010.11.027] [PMID: 21123063]
[152]
Dickens, M.P.; Roxburgh, P.; Hock, A.; Mezna, M.; Kellam, B.; Vousden, K.H.; Fischer, P.M. 5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2. Bioorg. Med. Chem., 2013, 21(22), 6868-6877.
[http://dx.doi.org/10.1016/j.bmc.2013.09.038] [PMID: 24113239]
[http://dx.doi.org/10.1016/j.bmc.2013.09.038] [PMID: 24113239]
[153]
ClinicalTrials.gov identifiers for RG7112: NCT00559533,
NCT00623870, NCT01677780, NCT01164033, NCT01-
605526, NCT01143740, NCT02407080 and NCT016-
35296, 2013.
[154]
Ding, Q.; Zhang, Z.; Liu, J.J.; Jiang, N.; Zhang, J.; Ross, T.M.; Chu, X.J.; Bartkovitz, D.; Podlaski, F.; Janson, C.; Tovar, C.; Filipovic, Z.M.; Higgins, B.; Glenn, K.; Packman, K.; Vassilev, L.T.; Graves, B. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J. Med. Chem., 2013, 56(14), 5979-5983.
[http://dx.doi.org/10.1021/jm400487c] [PMID: 23808545]
[http://dx.doi.org/10.1021/jm400487c] [PMID: 23808545]
[155]
Siu, L.L.; Italiano, A.; Miller, W.H., Jr; Blay, J.Y.; Gietema, J.A.; Bang, Y.J.; Mileshkin, L.R.; Hirte, H.W.; Reckner, M.; Higgins, B.; Jukofsky, L.; Blotner, S.; Zhi, J.; Middleton, S.; Nichols, G.L.; Chen, L.C. Phase 1 dose escalation, food effect, and biomarker study of RG7388, a more potent second-generation MDM2 antagonist, in patients (pts) with solid tumors. J. Clin. Oncol., 2014, 32, 2535.
[http://dx.doi.org/10.1200/jco.2014.32.15_suppl.2535]
[http://dx.doi.org/10.1200/jco.2014.32.15_suppl.2535]
[156]
ClinicalTrials.gov identifiers for RG7388: NCT02407080,
NCT02828930, NCT01901172, NCT01462175, NCT0-2633059, NCT02545283, NCT02624986, NCT02670044,
CRUKE/12/032 and NCT01773408, 2013.
[157]
Wang, S.; Sun, W.; Zhao, Y.; McEachern, D.; Meaux, I.; Barrière, C.; Stuckey, J.A.; Meagher, J.L.; Bai, L.; Liu, L.; Hoffman-Luca, C.G.; Lu, J.; Shangary, S.; Yu, S.; Bernard, D.; Aguilar, A.; Dos-Santos, O.; Besret, L.; Guerif, S.; Pannier, P.; Gorge-Bernat, D.; Debussche, L. SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Cancer Res., 2014, 74(20), 5855-5865.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0799] [PMID: 25145672]
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0799] [PMID: 25145672]
[158]
ClinicalTrials.gov identifiers for AMG 232: NCT0-
1723020, NCT02016729, NCT02110355 and NCT030-
31730.,, 2013.
Article Metrics
![Wayfinder Image](/images/wayfinder.jpg)