Small Molecules Targeting Mutant P53: A Promising Approach for Cancer Treatment

Author(s): Elizabeth A. Lopes, Sara Gomes, Lucília Saraiva, Maria M.M. Santos*

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 41 , 2019

DOI : 10.2174/0929867325666181116124308

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Abstract:

More than half of all human tumors express mutant forms of p53, with the ovary, lung, pancreas, and colorectal cancers among the tumor types that display the highest prevalence of p53 mutations. In addition, the expression of mutant forms of p53 in tumors is associated with poor prognosis due to increased chemoresistance and invasiveness. Therefore, the pharmacological restoration of wild-type-like activity to mutant p53 arises as a promising therapeutic strategy against cancer. This review is focused on the most relevant mutant p53 small molecule reactivators described to date. Despite some of them have entered into clinical trials, none has reached the clinic, which emphasizes that new pharmacological alternatives, particularly with higher selectivity and lower adverse toxic side effects, are still required.

Keywords: Cancer, chemotherapy, p53 tumor suppressor, reactivators, mutant p53, small molecules.

[1]
Bieging, K.T.; Mello, S.S.; Attardi, L.D. Unravelling mechanisms of p53-mediated tumour suppression. Nat. Rev. Cancer, 2014, 14(5), 359-370.
[http://dx.doi.org/10.1038/nrc3711] [PMID: 24739573]
[2]
Kruiswijk, F.; Labuschagne, C.F.; Vousden, K.H. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat. Rev. Mol. Cell Biol., 2015, 16(7), 393-405.
[http://dx.doi.org/10.1038/nrm4007] [PMID: 26122615]
[3]
Vousden, K.H.; Lane, D.P. p53 in health and disease. Nat. Rev. Mol. Cell Biol., 2007, 8(4), 275-283.
[http://dx.doi.org/10.1038/nrm2147] [PMID: 17380161]
[4]
Zilfou, J.T.; Lowe, S.W. Tumor suppressive functions of p53. Cold Spring Harb. Perspect. Biol., 2009, 1(5)a001883
[http://dx.doi.org/10.1101/cshperspect.a001883] [PMID: 20066118]
[5]
Menendez, D.; Inga, A.; Resnick, M.A. The expanding universe of p53 targets. Nat. Rev. Cancer, 2009, 9(10), 724-737.
[http://dx.doi.org/10.1038/nrc2730] [PMID: 19776742]
[6]
Menendez, D.; Inga, A.; Resnick, M.A. Potentiating the p53 network. Discov. Med., 2010, 10(50), 94-100.
[PMID: 20670604]
[7]
Smeenk, L.; van Heeringen, S.J.; Koeppel, M.; van Driel, M.A.; Bartels, S.J.; Akkers, R.C.; Denissov, S.; Stunnenberg, H.G.; Lohrum, M. Characterization of genome-wide p53-binding sites upon stress response. Nucleic Acids Res., 2008, 36(11), 3639-3654.
[http://dx.doi.org/10.1093/nar/gkn232] [PMID: 18474530]
[8]
Tebaldi, T.; Zaccara, S.; Alessandrini, F.; Bisio, A.; Ciribilli, Y.; Inga, A. Whole-genome cartography of p53 response elements ranked on transactivation potential. BMC Genomics, 2015, 16, 464.
[http://dx.doi.org/10.1186/s12864-015-1643-9] [PMID: 26081755]
[9]
Vyas, P.; Beno, I.; Xi, Z.; Stein, Y.; Golovenko, D.; Kessler, N.; Rotter, V.; Shakked, Z.; Haran, T.E. Diverse p53/DNA binding modes expand the repertoire of p53 response elements. Proc. Natl. Acad. Sci. USA, 2017, 114(40), 10624-10629.
[http://dx.doi.org/10.1073/pnas.1618005114] [PMID: 28912355]
[10]
Ribeiro, C.J.; Rodrigues, C.M.; Moreira, R.; Santos, M.M. Chemical variations on the p53 reactivation theme. Pharmaceuticals (Basel), 2016, 9(2), 25.
[http://dx.doi.org/10.3390/ph9020025] [PMID: 27187415]
[11]
Lemos, A.; Leão, M.; Soares, J.; Palmeira, A.; Pinto, M.; Saraiva, L.; Sousa, M.E. Medicinal chemistry strategies to disrupt the p53-MDM2/MDMX interaction. Med. Res. Rev., 2016, 36(5), 789-844.
[http://dx.doi.org/10.1002/med.21393] [PMID: 27302609]
[12]
Bykov, V.J.N.; Eriksson, S.E.; Bianchi, J.; Wiman, K.G. Targeting mutant p53 for efficient cancer therapy. Nat. Rev. Cancer, 2018, 18(2), 89-102.
[http://dx.doi.org/10.1038/nrc.2017.109] [PMID: 29242642]
[13]
Soares, J.; Loureiro, J.B.; Saraiva, L. Keeping p53 active: The challenge of cancer therapy. In: Advances in Drug Discovery and Development; Avid Science, 2017.
[14]
Laptenko, O.; Prives, C. Transcriptional regulation by p53: one protein, many possibilities. Cell Death Differ., 2006, 13(6), 951-961.
[http://dx.doi.org/10.1038/sj.cdd.4401916] [PMID: 16575405]
[15]
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]
[16]
Chan, W.M.; Siu, W.Y.; Lau, A.; Poon, R.Y. How many mutant p53 molecules are needed to inactivate a tetramer? Mol. Cell. Biol., 2004, 24(8), 3536-3551.
[http://dx.doi.org/10.1128/MCB.24.8.3536-3551.2004] [PMID: 15060172]
[17]
Chène, P. In vitro analysis of the dominant negative effect of p53 mutants. J. Mol. Biol., 1998, 281(2), 205-209.
[http://dx.doi.org/10.1006/jmbi.1998.1897] [PMID: 9698540]
[18]
Petitjean, A.; Mathe, E.; Kato, S.; Ishioka, C.; Tavtigian, S.V.; Hainaut, P.; Olivier, M. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum. Mutat., 2007, 28(6), 622-629.
[http://dx.doi.org/10.1002/humu.20495] [PMID: 17311302]
[19]
Xu, J.; Reumers, J.; Couceiro, J.R.; De Smet, F.; Gallardo, R.; Rudyak, S.; Cornelis, A.; Rozenski, J.; Zwolinska, A.; Marine, J.C.; Lambrechts, D.; Suh, Y.A.; Rousseau, F.; Schymkowitz, J. Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. Nat. Chem. Biol., 2011, 7(5), 285-295.
[http://dx.doi.org/10.1038/nchembio.546] [PMID: 21445056]
[20]
Di Como, C.J.; Gaiddon, C.; Prives, C. p73 function is inhibited by tumor-derived p53 mutants in mammalian cells. Mol. Cell. Biol., 1999, 19(2), 1438-1449.
[http://dx.doi.org/10.1128/MCB.19.2.1438] [PMID: 9891077]
[21]
Gaiddon, C.; Lokshin, M.; Ahn, J.; Zhang, T.; Prives, C. A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Mol. Cell. Biol., 2001, 21(5), 1874-1887.
[http://dx.doi.org/10.1128/MCB.21.5.1874-1887.2001] [PMID: 11238924]
[22]
Monti, P.; Campomenosi, P.; Ciribilli, Y.; Iannone, R.; Aprile, A.; Inga, A.; Tada, M.; Menichini, P.; Abbondandolo, A.; Fronza, G. Characterization of the p53 mutants ability to inhibit p73 beta transactivation using a yeast-based functional assay. Oncogene, 2003, 22(34), 5252-5260.
[http://dx.doi.org/10.1038/sj.onc.1206511] [PMID: 12917626]
[23]
Oren, M.; Rotter, V. Mutant p53 gain-of-function in cancer. Cold Spring Harb. Perspect. Biol., 2010, 2(2)a001107
[http://dx.doi.org/10.1101/cshperspect.a001107] [PMID: 20182618]
[24]
Adorno, M.; Cordenonsi, M.; Montagner, M.; Dupont, S.; Wong, C.; Hann, B.; Solari, A.; Bobisse, S.; Rondina, M.B.; Guzzardo, V.; Parenti, A.R.; Rosato, A.; Bicciato, S.; Balmain, A.; Piccolo, S.A. Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell, 2009, 137(1), 87-98.
[http://dx.doi.org/10.1016/j.cell.2009.01.039] [PMID: 19345189]
[25]
Bergamaschi, D.; Gasco, M.; Hiller, L.; Sullivan, A.; Syed, N.; Trigiante, G.; Yulug, I.; Merlano, M.; Numico, G.; Comino, A.; Attard, M.; Reelfs, O.; Gusterson, B.; Bell, A.K.; Heath, V.; Tavassoli, M.; Farrell, P.J.; Smith, P.; Lu, X.; Crook, T. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell, 2003, 3(4), 387-402.
[http://dx.doi.org/10.1016/S1535-6108(03)00079-5] [PMID: 12726864]
[26]
Muller, P.A.; Caswell, P.T.; Doyle, B.; Iwanicki, M.P.; Tan, E.H.; Karim, S.; Lukashchuk, N.; Gillespie, D.A.; Ludwig, R.L.; Gosselin, P.; Cromer, A.; Brugge, J.S.; Sansom, O.J.; Norman, J.C.; Vousden, K.H. Mutant p53 drives invasion by promoting integrin recycling. Cell, 2009, 139(7), 1327-1341.
[http://dx.doi.org/10.1016/j.cell.2009.11.026] [PMID: 20064378]
[27]
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]
[28]
Lawrence, M.S.; Stojanov, P.; Mermel, C.H.; Robinson, J.T.; Garraway, L.A.; Golub, T.R.; Meyerson, M.; Gabriel, S.B.; Lander, E.S.; Getz, G. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature, 2014, 505(7484), 495-501.
[http://dx.doi.org/10.1038/nature12912] [PMID: 24390350]
[29]
Ablain, J.; Poirot, B.; Esnault, C.; Lehmann-Che, J.; de Thé, H. p53 as an effector or inhibitor of therapy response. Cold Spring Harb. Perspect. Med., 2015, 6(1)a026260
[http://dx.doi.org/10.1101/cshperspect.a026260] [PMID: 26637438]
[30]
Lin, C.H.; Chen, I.C.; Huang, C.S.; Hu, F.C.; Kuo, W.H.; Kuo, K.T.; Wang, C.C.; Wu, P.F.; Chang, D.Y.; Wang, M.Y.; Chang, C.H.; Chen, W.W.; Lu, Y.S.; Cheng, A.L. TP53 mutational analysis enhances the prognostic accuracy of IHC4 and PAM50 assays. Sci. Rep., 2015, 5, 17879.
[http://dx.doi.org/10.1038/srep17879] [PMID: 26671300]
[31]
Lu, C.; El-Deiry, W.S. Targeting p53 for enhanced radio- and chemo-sensitivity. Apoptosis, 2009, 14(4), 597-606.
[http://dx.doi.org/10.1007/s10495-009-0330-1] [PMID: 19259822]
[32]
Pirollo, K.F.; Bouker, K.B.; Chang, E.H. Does p53 status influence tumor response to anticancer therapies? Anticancer Drugs, 2000, 11(6), 419-432.
[http://dx.doi.org/10.1097/00001813-200007000-00002] [PMID: 11001382]
[33]
Zhou, G.; Liu, Z.; Myers, J.N. TP53 mutations in head and neck squamous cell carcinoma and their impact on disease progression and treatment response. J. Cell. Biochem., 2016, 117(12), 2682-2692.
[http://dx.doi.org/10.1002/jcb.25592] [PMID: 27166782]
[34]
Lowe, S.W.; Ruley, H.E.; Jacks, T.; Housman, D.E. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell, 1993, 74(6), 957-967.
[http://dx.doi.org/10.1016/0092-8674(93)90719-7] [PMID: 8402885]
[35]
Petitjean, A.; Achatz, M.I.W.; Borresen-Dale, A.L.; Hainaut, P.; Olivier, M. TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene, 2007, 26(15), 2157-2165.
[http://dx.doi.org/10.1038/sj.onc.1210302] [PMID: 17401424]
[36]
Parrales, A.; Iwakuma, T. Targeting oncogenic mutant p53 for cancer therapy. Front. Oncol., 2015, 5(288), 288.
[http://dx.doi.org/10.3389/fonc.2015.00288] [PMID: 26732534]
[37]
Mantovani, F.; Walerych, D.; Sal, G.D. Targeting mutant p53 in cancer: a long road to precision therapy. FEBS J., 2017, 284(6), 837-850.
[http://dx.doi.org/10.1111/febs.13948] [PMID: 27808469]
[38]
Foster, B.A.; Coffey, H.A.; Morin, M.J.; Rastinejad, F. Pharmacological rescue of mutant p53 conformation and function. Science, 1999, 286(5449), 2507-2510.
[http://dx.doi.org/10.1126/science.286.5449.2507] [PMID: 10617466]
[39]
Luu, Y.; Bush, J.; Cheung, K-J., Jr; Li, G. The p53 stabilizing compound CP-31398 induces apoptosis by activating the intrinsic Bax/mitochondrial/caspase-9 pathway. Exp. Cell Res., 2002, 276(2), 214-222.
[http://dx.doi.org/10.1006/excr.2002.5526] [PMID: 12027451]
[40]
Takimoto, R.; Wang, W.; Dicker, D.T.; Rastinejad, F.; Lyssikatos, J.; el-Deiry, W.S. The mutant p53-conformation modifying drug, CP-31398, can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein. Cancer Biol. Ther., 2002, 1(1), 47-55.
[http://dx.doi.org/10.4161/cbt.1.1.41] [PMID: 12174820]
[41]
Wang, W.; Takimoto, R.; Rastinejad, F.; El-Deiry, W.S. Stabilization of p53 by CP-31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 20 or MDM2 binding. Mol. Cell. Biol., 2003, 23(6), 2171-2181.
[http://dx.doi.org/10.1128/MCB.23.6.2171-2181.2003] [PMID: 12612087]
[42]
Rippin, T.M.; Bykov, V.J.; Freund, S.M.; Selivanova, G.; Wiman, K.G.; Fersht, A.R. Characterization of the p53-rescue drug CP-31398 in vitro and in living cells. Oncogene, 2002, 21(14), 2119-2129.
[http://dx.doi.org/10.1038/sj.onc.1205362] [PMID: 11948395]
[43]
Wischhusen, J.; Naumann, U.; Ohgaki, H.; Rastinejad, F.; Weller, M. CP-31398, a novel p53-stabilizing agent, induces p53-dependent and p53-independent glioma cell death. Oncogene, 2003, 22(51), 8233-8245.
[http://dx.doi.org/10.1038/sj.onc.1207198] [PMID: 14614447]
[44]
Arihara, Y.; Takada, K.; Kamihara, Y.; Hayasaka, N.; Nakamura, H.; Murase, K.; Ikeda, H.; Iyama, S.; Sato, T.; Miyanishi, K.; Kobune, M.; Kato, J. Small molecule CP-31398 induces reactive oxygen species-dependent apoptosis in human multiple myeloma. Oncotarget, 2017, 8(39), 65889-65899.
[http://dx.doi.org/10.18632/oncotarget.19508] [PMID: 29029480]
[45]
Weinmann, L.; Wischhusen, J.; Demma, M.J.; Naumann, U.; Roth, P.; Dasmahapatra, B.; Weller, M. A novel p53 rescue compound induces p53-dependent growth arrest and sensitises glioma cells to Apo2L/TRAIL-induced apoptosis. Cell Death Differ., 2008, 15(4), 718-729.
[http://dx.doi.org/10.1038/sj.cdd.4402301] [PMID: 18202704]
[46]
Demma, M.J.; Wong, S.; Maxwell, E.; Dasmahapatra, B. CP-31398 restores DNA-binding activity to mutant p53 in vitro but does not affect p53 homologs p63 and p73. J. Biol. Chem., 2004, 279(44), 45887-45896.
[http://dx.doi.org/10.1074/jbc.M401854200] [PMID: 15308639]
[47]
Demma, M.; Maxwell, E.; Ramos, R.; Liang, L.; Li, C.; Hesk, D.; Rossman, R.; Mallams, A.; Doll, R.; Liu, M.; Seidel-Dugan, C.; Bishop, W.R.; Dasmahapatra, B. SCH529074, a small molecule activator of mutant p53, which binds p53 DNA binding domain (DBD), restores growth-suppressive function to mutant p53 and interrupts HDM2-mediated ubiquitination of wild type p53. J. Biol. Chem., 2010, 285(14), 10198-10212.
[http://dx.doi.org/10.1074/jbc.M109.083469] [PMID: 20124408]
[48]
Bykov, V.J.; Issaeva, N.; Shilov, A.; Hultcrantz, M.; Pugacheva, E.; Chumakov, P.; Bergman, J.; Wiman, K.G.; Selivanova, G. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat. Med., 2002, 8(3), 282-288.
[http://dx.doi.org/10.1038/nm0302-282] [PMID: 11875500]
[49]
Bykov, V.J.; Issaeva, N.; Selivanova, G.; Wiman, K.G. Mutant p53-dependent growth suppression distinguishes PRIMA-1 from known anticancer drugs: a statistical analysis of information in the National Cancer Institute database. Carcinogenesis, 2002, 23(12), 2011-2018.
[http://dx.doi.org/10.1093/carcin/23.12.2011] [PMID: 12507923]
[50]
Lambert, J.M.; Gorzov, P.; Veprintsev, D.B.; Söderqvist, M.; Segerbäck, D.; Bergman, J.; Fersht, A.R.; Hainaut, P.; Wiman, K.G.; Bykov, V.J. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell, 2009, 15(5), 376-388.
[http://dx.doi.org/10.1016/j.ccr.2009.03.003] [PMID: 19411067]
[51]
Nahi, H.; Lehmann, S.; Mollgard, L.; Bengtzen, S.; Selivanova, G.; Wiman, K.G.; Paul, C.; Merup, M. Effects of PRIMA-1 on chronic lymphocytic leukaemia cells with and without hemizygous p53 deletion. Br. J. Haematol., 2004, 127(3), 285-291.
[http://dx.doi.org/10.1111/j.1365-2141.2004.05210.x] [PMID: 15491287]
[52]
Nahi, H.; Merup, M.; Lehmann, S.; Bengtzen, S.; Möllgård, L.; Selivanova, G.; Wiman, K.G.; Paul, C. PRIMA-1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion. Br. J. Haematol., 2006, 132(2), 230-236.
[http://dx.doi.org/10.1111/j.1365-2141.2005.05851.x] [PMID: 16398657]
[53]
Bykov, V.J.; Zache, N.; Stridh, H.; Westman, J.; Bergman, J.; Selivanova, G.; Wiman, K.G. PRIMA-1(MET) synergizes with cisplatin to induce tumor cell apoptosis. Oncogene, 2005, 24(21), 3484-3491.
[http://dx.doi.org/10.1038/sj.onc.1208419] [PMID: 15735745]
[54]
Cheok, C.F.; Verma, C.S.; Baselga, J.; Lane, D.P. Translating p53 into the clinic. Nat. Rev. Clin. Oncol., 2011, 8(1), 25-37.
[http://dx.doi.org/10.1038/nrclinonc.2010.174] [PMID: 20975744]
[55]
Lehmann, S.; Bykov, V.J.; Ali, D.; Andrén, O.; Cherif, H.; Tidefelt, U.; Uggla, B.; Yachnin, J.; Juliusson, G.; Moshfegh, A.; Paul, C.; Wiman, K.G.; Andersson, P.O. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J. Clin. Oncol., 2012, 30(29), 3633-3639.
[http://dx.doi.org/10.1200/JCO.2011.40.7783] [PMID: 22965953]
[56]
Ali, D.; Jönsson-Videsäter, K.; Deneberg, S.; Bengtzén, S.; Nahi, H.; Paul, C.; Lehmann, S. APR-246 exhibits anti-leukemic activity and synergism with conventional chemotherapeutic drugs in acute myeloid leukemia cells. Eur. J. Haematol., 2011, 86(3), 206-215.
[http://dx.doi.org/10.1111/j.1600-0609.2010.01557.x] [PMID: 21114538]
[57]
Liang, Y.; Mafuvadze, B.; Besch-Williford, C.; Hyder, S.M. A combination of p53-activating APR-246 and phosphatidylserine-targeting antibody potently inhibits tumor development in hormone-dependent mutant p53-expressing breast cancer xenografts. Breast Cancer (Dove Med. Press), 2018, 10, 53-67.
[http://dx.doi.org/10.2147/BCTT.S156285] [PMID: 29606888]
[58]
Bykov, V.J.; Issaeva, N.; Zache, N.; Shilov, A.; Hultcrantz, M.; Bergman, J.; Selivanova, G.; Wiman, K.G. Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs. J. Biol. Chem., 2005, 280(34), 30384-30391.
[http://dx.doi.org/10.1074/jbc.M501664200] [PMID: 15998635]
[59]
Saha, M.N.; Chen, Y.; Chen, M.H.; Chen, G.; Chang, H. Small molecule MIRA-1 induces in vitro and in vivo anti-myeloma activity and synergizes with current anti-myeloma agents. Br. J. Cancer, 2014, 110(9), 2224-2231.
[http://dx.doi.org/10.1038/bjc.2014.164] [PMID: 24691427]
[60]
Bou-Hanna, C.; Jarry, A.; Lode, L.; Schmitz, I.; Schulze-Osthoff, K.; Kury, S.; Bezieau, S.; Mosnier, J-F.; Laboisse, C.L. Acute cytotoxicity of MIRA-1/NSC19630, a mutant p53-reactivating small molecule, against human normal and cancer cells via a caspase-9-dependent apoptosis. Cancer Lett., 2015, 359(2), 211-217.
[http://dx.doi.org/10.1016/j.canlet.2015.01.014] [PMID: 25617798]
[61]
Zache, N.; Lambert, J.M.; Rökaeus, N.; Shen, J.; Hainaut, P.; Bergman, J.; Wiman, K.G.; Bykov, V.J. Mutant p53 targeting by the low molecular weight compound STIMA-1. Mol. Oncol., 2008, 2(1), 70-80.
[http://dx.doi.org/10.1016/j.molonc.2008.02.004] [PMID: 19383329]
[62]
Boeckler, F.M.; Joerger, A.C.; Jaggi, G.; Rutherford, T.J.; Veprintsev, D.B.; Fersht, A.R. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc. Natl. Acad. Sci. USA, 2008, 105(30), 10360-10365.
[http://dx.doi.org/10.1073/pnas.0805326105] [PMID: 18650397]
[63]
Yu, X.; Vazquez, A.; Levine, A.J.; Carpizo, D.R. Allele-specific p53 mutant reactivation. Cancer Cell, 2012, 21(5), 614-625.
[http://dx.doi.org/10.1016/j.ccr.2012.03.042] [PMID: 22624712]
[64]
Yu, X.; Blanden, A.R.; Narayanan, S.; Jayakumar, L.; Lubin, D.; Augeri, D.; Kimball, S.D.; Loh, S.N.; Carpizo, D.R. Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc-metallochaperone based mechanism. Oncotarget, 2014, 5(19), 8879-8892.
[http://dx.doi.org/10.18632/oncotarget.2432] [PMID: 25294809]
[65]
Yu, X.; Blanden, A.R.; Tsang, A.; Zaman, S.; Liu, Y. gilleran, J.; Bencivenga, A. F.; Kimball, S. D.; Loh, S. N.; Carpizo, D. R. Thiosemicarbazones functioning as zinc metallochaperones to reactivate mutant p53. Mol. Pharmacol., 2017, 91(6), 567-575.
[http://dx.doi.org/10.1124/mol.116.107409] [PMID: 28320780]
[66]
Salim, K.Y.; Maleki Vareki, S.; Danter, W.R.; Koropatnick, J. COTI-2, a novel small molecule that is active against multiple human cancer cell lines in vitro and in vivo. Oncotarget, 2016, 7(27), 41363-41379.
[http://dx.doi.org/10.18632/oncotarget.9133] [PMID: 27150056]
[67]
Silver, N.L.; Osman, A.A.; Patel, A.A.; Tanaka, N.; Tang, L.; Zhou, G.; Myers, J.N. A novel third generation thiosemicarbazone, COTI-2, is highly effective in killing head and neck squamous cell carcinomas (HNSCC) bearing a variety of TP53 mutations. In: Intl. J. Rad. Oncol. Biol. Phys; Elsevier, 2016. Vol. 94(4), p. 942.
[http://dx.doi.org/10.1016/j.ijrobp.2015.12.272]
[68]
Study of COTI-2 for the treatment of gynecologic malignancies and head and neck squamous cell carcinoma (COTI2-101), Available from: https://clinicaltrials.gov/ct2/show/ (Accessed Date:8 June, 2018)
[69]
Liu, X.; Wilcken, R.; Joerger, A.C.; Chuckowree, I.S.; Amin, J.; Spencer, J.; Fersht, A.R. Small molecule induced reactivation of mutant p53 in cancer cells. Nucleic Acids Res., 2013, 41(12), 6034-6044.
[http://dx.doi.org/10.1093/nar/gkt305] [PMID: 23630318]
[70]
Kuo, Y-C.; Kuo, P-L.; Hsu, Y-L.; Cho, C-Y.; Lin, C-C. Ellipticine induces apoptosis through p53-dependent pathway in human hepatocellular carcinoma HepG2 cells. Life Sci., 2006, 78(22), 2550-2557.
[http://dx.doi.org/10.1016/j.lfs.2005.10.041] [PMID: 16337242]
[71]
Stiborová, M.; Indra, R.; Moserová, M.; Frei, E.; Schmeiser, H.H.; Kopka, K.; Phillips, D.H.; Arlt, V.M. NADH: Cytochrome b5 reductase and cytochrome b5 can act as sole electron donors to human cytochrome P450 1A1-mediated oxidation and DNA adduct formation by benzo[a]pyrene. Chem. Res. Toxicol., 2016, 29(8), 1325-1334.
[http://dx.doi.org/10.1021/acs.chemrestox.6b00143] [PMID: 27404282]
[72]
Peng, Y.; Li, C.; Chen, L.; Sebti, S.; Chen, J. Rescue of mutant p53 transcription function by ellipticine. Oncogene, 2003, 22(29), 4478-4487.
[http://dx.doi.org/10.1038/sj.onc.1206777] [PMID: 12881704]
[73]
Ohashi, M.; Oki, T. Overview oncologic, endocrine & metabolic: Oncologic, endocrine & metabolic: Ellipticine and related anticancer agents. Expert Opin. Ther. Pat., 1996, 6(12), 1285-1294.
[http://dx.doi.org/10.1517/13543776.6.12.1285]
[74]
Miller, C.M.; McCarthy, F.O. Isolation, biological activity and synthesis of the natural product ellipticine and related pyridocarbazoles. RSC Advances, 2012, 2(24), 8883-8918.
[http://dx.doi.org/10.1039/c2ra20584j]
[75]
Sugikawa, E.; Hosoi, T.; Yazaki, N.; Gamanuma, M.; Nakanishi, N.; Ohashi, M. Mutant p53 mediated induction of cell cycle arrest and apoptosis at G1 phase by 9-hydroxyellipticine. Anticancer Res., 1999, 19(4B), 3099-3108.
[PMID: 10652599]
[76]
Mizumoto, K.; Sato, N.; Kusumoto, M.; Niiyama, H.; Maehara, N.; Nishio, S.; Li, Z.; Ogawa, T.; Tanaka, M. Diverse effects of 9-hydroxyellipticine on the chemosensitivity of human pancreatic cancer cells harboring p53 mutations. Cancer Lett., 2000, 149(1-2), 85-94.
[http://dx.doi.org/10.1016/S0304-3835(99)00345-6] [PMID: 10737712]
[77]
Paoletti, C.; Le Pecq, J-B.; Dat-Xuong, N.; Juret, P.; Garnier, H.; Amiel, J-L.; Rouesse, J. Antitumor activity, pharmacology, and toxicity of ellipticines, ellipticinium, and 9-hydroxy derivatives: preliminary clinical trials of 2-methyl-9-hydroxy ellipticinium (NSC 264-137). In: Cancer Chemo-and Immunopharmacology; Springer, 1980; pp. 107-123.
[http://dx.doi.org/10.1007/978-3-642-81488-4_15]
[78]
Stiborová, M.; Černá, V.; Moserová, M.; Mrízová, I.; Arlt, V.M.; Frei, E. The anticancer drug ellipticine activated with cytochrome P450 mediates DNA damage determining its pharmacological efficiencies: studies with rats, hepatic cytochrome P450 reductase null (HRN™) mice and pure enzymes. Int. J. Mol. Sci., 2014, 16(1), 284-306.
[http://dx.doi.org/10.3390/ijms16010284] [PMID: 25547492]
[79]
Wassman, C.D.; Baronio, R.; Demir, Ö.; Wallentine, B.D.; Chen, C-K.; Hall, L.V.; Salehi, F.; Lin, D-W.; Chung, B.P.; Hatfield, G.W.; Richard Chamberlin, A.; Luecke, H.; Lathrop, R.H.; Kaiser, P.; Amaro, R.E. Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53. Nat. Commun., 2013, 4, 1407.
[http://dx.doi.org/10.1038/ncomms2361] [PMID: 23360998]
[80]
Hiraki, M.; Hwang, S-Y.; Cao, S.; Ramadhar, T.R.; Byun, S.; Yoon, K.W.; Lee, J.H.; Chu, K.; Gurkar, A.U.; Kolev, V.; Zhang, J.; Namba, T.; Murphy, M.E.; Newman, D.J.; Mandinova, A.; Clardy, J.; Lee, S.W. Small-molecule reactivation of mutant p53 to wild-type-like p53 through the p53-Hsp40 regulatory axis. Chem. Biol., 2015, 22(9), 1206-1216.
[http://dx.doi.org/10.1016/j.chembiol.2015.07.016] [PMID: 26320861]
[81]
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]
[82]
Bauer, M.R.; Joerger, A.C.; Fersht, A.R. 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells. Proc. Natl. Acad. Sci. USA, 2016, 113(36), E5271-E5280.
[http://dx.doi.org/10.1073/pnas.1610421113] [PMID: 27551077]
[83]
Synnott, N.C.; Bauer, M.R.; Madden, S.; Murray, A.; Klinger, R.; O’Donovan, N.; O’Connor, D.; Gallagher, W.M.; Crown, J.; Fersht, A.R.; Duffy, M.J. Mutant p53 as a therapeutic target for the treatment of triple-negative breast cancer: Preclinical investigation with the anti-p53 drug, PK11007. Cancer Lett., 2018, 414, 99-106.
[http://dx.doi.org/10.1016/j.canlet.2017.09.053] [PMID: 29069577]
[84]
Soares, J.; Raimundo, L.; Pereira, N.A.; Monteiro, Â.; Gomes, S.; Bessa, C.; Pereira, C.; Queiroz, G.; Bisio, A.; Fernandes, J.; Gomes, C.; Reis, F.; Gonçalves, J.; Inga, A.; Santos, M.M.M.; Saraiva, L. Reactivation of wild-type and mutant p53 by tryptophanolderived oxazoloisoindolinone SLMP53-1, a novel anticancer small-molecule. Oncotarget, 2016, 7(4), 4326-4343.
[http://dx.doi.org/10.18632/oncotarget.6775] [PMID: 26735173]
[85]
Saraiva, L.H.A.; Santos, M.M.M.; Pereira, N.A.L.; Pereira, C.I.F.; Moreira, S.G.; Leão, M.V.C.F.; Monteiro, A.F.A.; Soares, J.O.G. Tryptophanol-derived oxazoloisoindolinones: small-molecule P53 activators. European patent PCT/IB2014/062617, US patent WO2014/207688 A1, 2017.
[86]
Selvendiran, K.; Kuppusamy, M.L.; Bratasz, A.; Tong, L.; Rivera, B.K.; Rink, C.; Sen, C.K.; Kálai, T.; Hideg, K.; Kuppusamy, P. Inhibition of vascular smooth-muscle cell proliferation and arterial restenosis by HO-3867, a novel synthetic curcuminoid, through up-regulation of PTEN expression. J. Pharmacol. Exp. Ther., 2009, 329(3), 959-966.
[http://dx.doi.org/10.1124/jpet.108.150367] [PMID: 19276401]
[87]
Madan, E.; Parker, T.M.; Bauer, M.R.; Dhiman, A.; Pelham, C.J.; Nagane, M.; Kuppusamy, M.L.; Holmes, M.; Holmes, T.R.; Shaik, K.; Shee, K.; Kiparoidze, S.; Smith, S.D.; Park, Y.A.; Gomm, J.J.; Jones, L.J.; Tomás, A.R.; Cunha, A.C.; Selvendiran, K.; Hansen, L.A.; Fersht, A.R.; Hideg, K.; Gogna, R.; Kuppusamy, P. The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53. J. Biol. Chem., 2018, 293(12), 4262-4276.
[http://dx.doi.org/10.1074/jbc.RA117.000950] [PMID: 29382728]


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VOLUME: 26
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Year: 2019
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DOI: 10.2174/0929867325666181116124308
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