Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Author(s): Qixun Feng, Honggao Duan, Xinglong Zhou, Yuning Wang, Jinda Zhang, Haoge Zhang, Guoliang Chen* and Xuefei Bao*

DOI: 10.2174/1389557523666230825100246

DownloadDownload PDF Flyer Cite As
DNA Methyltransferase 3A: A Significant Target for the Discovery of Inhibitors as Potent Anticancer Drugs

Page: [507 - 520] Pages: 14

  • * (Excluding Mailing and Handling)

Abstract

DNA methyltransferase (DNMT) is a conserved family of Cytosine methylases, which plays a crucial role in the regulation of Epigenetics. They have been considered promising therapeutic targets for cancer. Among the DNMT family, mutations in the DNMT3A subtype are particularly important in hematologic malignancies. The development of specific DNMT3A subtype inhibitors to validate the therapeutic potential of DNMT3A in certain diseases is a significant task. In this review, we summarized the small molecule inhibitors of DNMT3A discovered in recent years and their inhibitory activities, and classified them based on their inhibitory mechanisms.

Graphical Abstract

[1]
Moore, L.D.; Le, T.; Fan, G. DNA methylation and its basic function. Neuropsychopharmacology, 2013, 38(1), 23-38.
[http://dx.doi.org/10.1038/npp.2012.112] [PMID: 22781841]
[2]
You, J.S.; Jones, P.A. Cancer genetics and epigenetics: Two sides of the same coin? Cancer Cell, 2012, 22(1), 9-20.
[http://dx.doi.org/10.1016/j.ccr.2012.06.008] [PMID: 22789535]
[3]
Hoang, N.M.; Rui, L. DNA methyltransferases in hematological malignancies. J. Genet. Genom., 2020, 47(7), 361-372.
[http://dx.doi.org/10.1016/j.jgg.2020.04.006] [PMID: 32994141]
[4]
Zhang, H.; Ying, H.; Wang, X. Methyltransferase DNMT3B in leukemia. Leuk. Lymphoma, 2020, 61(2), 263-273.
[http://dx.doi.org/10.1080/10428194.2019.1666377] [PMID: 31547729]
[5]
Hamidi, T.; Singh, A.K.; Chen, T. Genetic alterations of DNA methylation machinery in human diseases. Epigenomics, 2015, 7(2), 247-265.
[http://dx.doi.org/10.2217/epi.14.80] [PMID: 25942534]
[6]
Li, E.; Zhang, Y. DNA methylation in mammals. Cold Spring Harb. Perspect. Biol., 2014, 6(5), a019133.
[http://dx.doi.org/10.1101/cshperspect.a019133] [PMID: 24789823]
[7]
Barau, J.; Teissandier, A.; Zamudio, N.; Roy, S.; Nalesso, V.; Hérault, Y.; Guillou, F.; Bourc’his, D. The DNA methyltransferase DNMT3C protects male germ cells from transposon activity. Science, 2016, 354(6314), 909-912.
[http://dx.doi.org/10.1126/science.aah5143] [PMID: 27856912]
[8]
Jia, D.; Jurkowska, R.Z.; Zhang, X.; Jeltsch, A.; Cheng, X. Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature, 2007, 449(7159), 248-251.
[http://dx.doi.org/10.1038/nature06146] [PMID: 17713477]
[9]
Fernández-Sanlés, A.; Sayols-Baixeras, S.; Subirana, I.; Sentí, M.; Pérez-Fernández, S.; de Castro Moura, M.; Esteller, M.; Marrugat, J.; Elosua, R. DNA methylation biomarkers of myocardial infarction and cardiovascular disease. Clin. Epigenet., 2021, 13(1), 86.
[http://dx.doi.org/10.1186/s13148-021-01078-6] [PMID: 33883000]
[10]
Teitell, M.; Richardson, B. Dna methylation in the immune system. Clin. Immunol., 2003, 109(1), 2-5.
[http://dx.doi.org/10.1016/S1521-6616(03)00224-9] [PMID: 14585270]
[11]
Weng, Y.L.; An, R.; Shin, J.; Song, H.; Ming, G. DNA modifications and neurological disorders. Neurotherapeutics, 2013, 10(4), 556-567.
[http://dx.doi.org/10.1007/s13311-013-0223-4] [PMID: 24150811]
[12]
Arguelles, A.O.; Meruvu, S.; Bowman, J.D.; Choudhury, M. Are epigenetic drugs for diabetes and obesity at our door step? Drug Discov. Today, 2016, 21(3), 499-509.
[http://dx.doi.org/10.1016/j.drudis.2015.12.001] [PMID: 26697737]
[13]
Michalak, E.M.; Burr, M.L.; Bannister, A.J.; Dawson, M.A. The roles of DNA, RNA and histone methylation in ageing and cancer. Nat. Rev. Mol. Cell Biol., 2019, 20(10), 573-589.
[http://dx.doi.org/10.1038/s41580-019-0143-1] [PMID: 31270442]
[14]
Gaudet, F.; Hodgson, J.G.; Eden, A.; Jackson-Grusby, L.; Dausman, J.; Gray, J.W.; Leonhardt, H.; Jaenisch, R. Induction of tumors in mice by genomic hypomethylation. Science, 2003, 300(5618), 489-492.
[http://dx.doi.org/10.1126/science.1083558] [PMID: 12702876]
[15]
Pan, Y.; Liu, G.; Zhou, F.; Su, B.; Li, Y. DNA methylation profiles in cancer diagnosis and therapeutics. Clin. Exp. Med., 2018, 18(1), 1-14.
[http://dx.doi.org/10.1007/s10238-017-0467-0] [PMID: 28752221]
[16]
Ali, S.R.; Jordan, M.; Nagarajan, P.; Amit, M. Nerve density and neuronal biomarkers in cancer. Cancers , 2022, 14(19), 4817.
[http://dx.doi.org/10.3390/cancers14194817] [PMID: 36230740]
[17]
Medina-Franco, J.L.; Méndez-Lucio, O.; Dueñas-González, A.; Yoo, J. Discovery and development of DNA methyltransferase inhibitors using in silico approaches. Drug Discov. Today, 2015, 20(5), 569-577.
[http://dx.doi.org/10.1016/j.drudis.2014.12.007] [PMID: 25526932]
[18]
Robertson, K.D.; Uzvolgyi, E.; Liang, G.; Talmadge, C.; Sumegi, J.; Gonzales, F.A.; Jones, P.A. The human DNA methyltransferases (DNMTs) 1, 3a and 3b: Coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res., 1999, 27(11), 2291-2298.
[http://dx.doi.org/10.1093/nar/27.11.2291] [PMID: 10325416]
[19]
Xie, S.; Wang, Z.; Okano, M.; Nogami, M.; Li, Y.; He, W.W.; Okumura, K.; Li, E. Cloning, expression and chromosome locations of the human DNMT3 gene family. Gene, 1999, 236(1), 87-95.
[http://dx.doi.org/10.1016/S0378-1119(99)00252-8] [PMID: 10433969]
[20]
Weisenberger, D.J.; Velicescu, M.; Preciado-Lopez, M.A.; Gonzales, F.A.; Tsai, Y.C.; Liang, G.; Jones, P.A. Identification and characterization of alternatively spliced variants of DNA methyltransferase 3a in mammalian cells. Gene, 2002, 298(1), 91-99.
[http://dx.doi.org/10.1016/S0378-1119(02)00976-9] [PMID: 12406579]
[21]
Yanagisawa, Y.; Ito, E.; Yuasa, Y.; Maruyama, K. The human DNA methyltransferases DNMT3A and DNMT3B have two types of promoters with different CpG contents. Biochim. Biophys. Acta Gene Struct. Expr., 2002, 1577(3), 457-465.
[http://dx.doi.org/10.1016/S0167-4781(02)00482-7] [PMID: 12359337]
[22]
Uysal, F.; Akkoyunlu, G.; Ozturk, S. Dynamic expression of DNA methyltransferases (DNMTs) in oocytes and early embryos. Biochimie, 2015, 116, 103-113.
[http://dx.doi.org/10.1016/j.biochi.2015.06.019] [PMID: 26143007]
[23]
Ren, W.; Gao, L.; Song, J. Structural basis of DNMT1 and DNMT3A-Mediated DNA methylation. Genes , 2018, 9(12), 620.
[http://dx.doi.org/10.3390/genes9120620] [PMID: 30544982]
[24]
Zeng, Y.; Chen, T. DNA methylation reprogramming during mammalian development. Genes , 2019, 10(4), 257.
[http://dx.doi.org/10.3390/genes10040257] [PMID: 30934924]
[25]
Chen, Z.; Zhang, Y. Role of mammalian DNA methyltransferases in development. Annu. Rev. Biochem., 2020, 89(1), 135-158.
[http://dx.doi.org/10.1146/annurev-biochem-103019-102815] [PMID: 31815535]
[26]
Baubec, T.; Colombo, D.F.; Wirbelauer, C.; Schmidt, J.; Burger, L.; Krebs, A.R.; Akalin, A.; Schübeler, D. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature, 2015, 520(7546), 243-247.
[http://dx.doi.org/10.1038/nature14176] [PMID: 25607372]
[27]
Dhayalan, A.; Rajavelu, A.; Rathert, P.; Tamas, R.; Jurkowska, R.Z.; Ragozin, S.; Jeltsch, A. The Dnmt3a PWWP domain reads histone 3 lysine 36 trimethylation and guides DNA methylation. J. Biol. Chem., 2010, 285(34), 26114-26120.
[http://dx.doi.org/10.1074/jbc.M109.089433] [PMID: 20547484]
[28]
Sendžikaitė G.; Hanna, C.W.; Stewart-Morgan, K.R.; Ivanova, E.; Kelsey, G. A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice. Nat. Commun., 2019, 10(1), 1884.
[http://dx.doi.org/10.1038/s41467-019-09713-w] [PMID: 31015495]
[29]
Guo, X.; Wang, L.; Li, J.; Ding, Z.; Xiao, J.; Yin, X.; He, S.; Shi, P.; Dong, L.; Li, G.; Tian, C.; Wang, J.; Cong, Y.; Xu, Y. Structural insight into autoinhibition and histone H3-induced activation of DNMT3A. Nature, 2015, 517(7536), 640-644.
[http://dx.doi.org/10.1038/nature13899] [PMID: 25383530]
[30]
Zhang, Y.; Jurkowska, R.; Soeroes, S.; Rajavelu, A.; Dhayalan, A.; Bock, I.; Rathert, P.; Brandt, O.; Reinhardt, R.; Fischle, W.; Jeltsch, A. Chromatin methylation activity of Dnmt3a and Dnmt3a/3L is guided by interaction of the ADD domain with the histone H3 tail. Nucleic Acids Res., 2010, 38(13), 4246-4253.
[http://dx.doi.org/10.1093/nar/gkq147] [PMID: 20223770]
[31]
Li, B.Z.; Huang, Z.; Cui, Q.Y.; Song, X.H.; Du, L.; Jeltsch, A.; Chen, P.; Li, G.; Li, E.; Xu, G.L. Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase. Cell Res., 2011, 21(8), 1172-1181.
[http://dx.doi.org/10.1038/cr.2011.92] [PMID: 21606950]
[32]
Saravanaraman, P.; Selvam, M.; Ashok, C.; Srijyothi, L.; Baluchamy, S. De novo methyltransferases: Potential players in diseases and new directions for targeted therapy. Biochimie, 2020, 176, 85-102.
[http://dx.doi.org/10.1016/j.biochi.2020.07.004] [PMID: 32659446]
[33]
Lyko, F. The DNA methyltransferase family: A versatile toolkit for epigenetic regulation. Nat. Rev. Genet., 2018, 19(2), 81-92.
[http://dx.doi.org/10.1038/nrg.2017.80] [PMID: 29033456]
[34]
Jeltsch, A.; Jurkowska, R.Z. Allosteric control of mammalian DNA methyltransferases – a new regulatory paradigm. Nucleic Acids Res., 2016, 44(18), 8556-8575.
[http://dx.doi.org/10.1093/nar/gkw723] [PMID: 27521372]
[35]
Gowher, H.; Jeltsch, A. Mammalian DNA methyltransferases: New discoveries and open questions. Biochem. Soc. Trans., 2018, 46(5), 1191-1202.
[http://dx.doi.org/10.1042/BST20170574] [PMID: 30154093]
[36]
Lukashevich, O.V.; Cherepanova, N.A.; Jurkovska, R.Z.; Jeltsch, A.; Gromova, E.S. Conserved motif VIII of murine DNA methyltransferase Dnmt3a is essential for methylation activity. BMC Biochem., 2016, 17(1), 7.
[http://dx.doi.org/10.1186/s12858-016-0064-y] [PMID: 27001594]
[37]
Fatemi, M.; Hermann, A.; Pradhan, S.; Jeltsch, A. The activity of the murine DNA methyltransferase Dnmt1 is controlled by interaction of the catalytic domain with the N-terminal part of the enzyme leading to an allosteric activation of the enzyme after binding to methylated DNA. J. Mol. Biol., 2001, 309(5), 1189-1199.
[http://dx.doi.org/10.1006/jmbi.2001.4709] [PMID: 11399088]
[38]
Margot, J.B.; Ehrenhofer-Murray, A.E.; Leonhardt, H. Interactions within the mammalian DNA methyltransferase family. BMC Mol. Biol., 2003, 4(1), 7.
[http://dx.doi.org/10.1186/1471-2199-4-7] [PMID: 12777184]
[39]
Xu, T.H.; Liu, M.; Zhou, X.E.; Liang, G.; Zhao, G.; Xu, H.E.; Melcher, K.; Jones, P.A. Structure of nucleosome-bound DNA methyltransferases DNMT3A and DNMT3B. Nature, 2020, 586(7827), 151-155.
[http://dx.doi.org/10.1038/s41586-020-2747-1] [PMID: 32968275]
[40]
Yarychkivska, O.; Tavana, O.; Gu, W.; Bestor, T.H. Independent functions of DNMT1 and USP7 at replication foci. Epigenet. Chromat., 2018, 11(1), 9.
[http://dx.doi.org/10.1186/s13072-018-0179-z] [PMID: 29482658]
[41]
Yarychkivska, O.; Shahabuddin, Z.; Comfort, N.; Boulard, M.; Bestor, T.H. BAH domains and a histone-like motif in DNA methyltransferase 1 (DNMT1) regulate de novo and maintenance methylation in vivo. J. Biol. Chem., 2018, 293(50), 19466-19475.
[http://dx.doi.org/10.1074/jbc.RA118.004612] [PMID: 30341171]
[42]
Yu, J.; Xie, T.; Wang, Z.; Wang, X.; Zeng, S.; Kang, Y.; Hou, T. DNA methyltransferases: Emerging targets for the discovery of inhibitors as potent anticancer drugs. Drug Discov. Today, 2019, 24(12), 2323-2331.
[http://dx.doi.org/10.1016/j.drudis.2019.08.006] [PMID: 31494187]
[43]
Zhang, Z.M.; Liu, S.; Lin, K.; Luo, Y.; Perry, J.J.; Wang, Y.; Song, J. Crystal structure of human DNA methyltransferase 1. J. Mol. Biol., 2015, 427(15), 2520-2531.
[http://dx.doi.org/10.1016/j.jmb.2015.06.001] [PMID: 26070743]
[44]
Xie, T.; Yu, J.; Fu, W.; Wang, Z.; Xu, L.; Chang, S.; Wang, E.; Zhu, F.; Zeng, S.; Kang, Y.; Hou, T. Insight into the selective binding mechanism of DNMT1 and DNMT3A inhibitors: A molecular simulation study. Phys. Chem. Chem. Phys., 2019, 21(24), 12931-12947.
[http://dx.doi.org/10.1039/C9CP02024A] [PMID: 31165133]
[45]
Ley, T.J.; Ding, L.; Walter, M.J.; McLellan, M.D.; Lamprecht, T.; Larson, D.E.; Kandoth, C.; Payton, J.E.; Baty, J.; Welch, J.; Harris, C.C.; Lichti, C.F.; Townsend, R.R.; Fulton, R.S.; Dooling, D.J.; Koboldt, D.C.; Schmidt, H.; Zhang, Q.; Osborne, J.R.; Lin, L.; O’Laughlin, M.; McMichael, J.F.; Delehaunty, K.D.; McGrath, S.D.; Fulton, L.A.; Magrini, V.J.; Vickery, T.L.; Hundal, J.; Cook, L.L.; Conyers, J.J.; Swift, G.W.; Reed, J.P.; Alldredge, P.A.; Wylie, T.; Walker, J.; Kalicki, J.; Watson, M.A.; Heath, S.; Shannon, W.D.; Varghese, N.; Nagarajan, R.; Westervelt, P.; Tomasson, M.H.; Link, D.C.; Graubert, T.A.; DiPersio, J.F.; Mardis, E.R.; Wilson, R.K. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med., 2010, 363(25), 2424-2433.
[http://dx.doi.org/10.1056/NEJMoa1005143] [PMID: 21067377]
[46]
Yan, X.J.; Xu, J.; Gu, Z.H.; Pan, C.M.; Lu, G.; Shen, Y.; Shi, J.Y.; Zhu, Y.M.; Tang, L.; Zhang, X.W.; Liang, W.X.; Mi, J.Q.; Song, H.D.; Li, K.Q.; Chen, Z.; Chen, S.J. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat. Genet., 2011, 43(4), 309-315.
[http://dx.doi.org/10.1038/ng.788] [PMID: 21399634]
[47]
Walter, M.J.; Ding, L.; Shen, D.; Shao, J.; Grillot, M.; McLellan, M.; Fulton, R.; Schmidt, H.; Kalicki-Veizer, J.; O’Laughlin, M.; Kandoth, C.; Baty, J.; Westervelt, P.; DiPersio, J.F.; Mardis, E.R.; Wilson, R.K.; Ley, T.J.; Graubert, T.A. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia, 2011, 25(7), 1153-1158.
[http://dx.doi.org/10.1038/leu.2011.44] [PMID: 21415852]
[48]
Xu, J.; Wang, Y.Y.; Dai, Y.J.; Zhang, W.; Zhang, W.N.; Xiong, S.M.; Gu, Z.H.; Wang, K.K.; Zeng, R.; Chen, Z.; Chen, S.J. DNMT3A Arg882 mutation drives chronic myelomonocytic leukemia through disturbing gene expression/DNA methylation in hematopoietic cells. Proc. Natl. Acad. Sci. USA, 2014, 111(7), 2620-2625.
[http://dx.doi.org/10.1073/pnas.1400150111] [PMID: 24497509]
[49]
Zhao, Z.; Wu, Q.; Cheng, J.; Qiu, X.; Zhang, J.; Fan, H. Depletion of DNMT3A suppressed cell proliferation and restored PTEN in hepatocellular carcinoma cell. J. Biomed. Biotechnol., 2010, 2010, 1-10.
[http://dx.doi.org/10.1155/2010/737535] [PMID: 20467490]
[50]
Mayle, A.; Yang, L.; Rodriguez, B.; Zhou, T.; Chang, E.; Curry, C.V.; Challen, G.A.; Li, W.; Wheeler, D.; Rebel, V.I.; Goodell, M.A. Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation. Blood, 2015, 125(4), 629-638.
[http://dx.doi.org/10.1182/blood-2014-08-594648] [PMID: 25416277]
[51]
Yang, L.; Rodriguez, B.; Mayle, A.; Park, H.J.; Lin, X.; Luo, M.; Jeong, M.; Curry, C.V.; Kim, S.B.; Ruau, D.; Zhang, X.; Zhou, T.; Zhou, M.; Rebel, V.I.; Challen, G.A.; Göttgens, B.; Lee, J.S.; Rau, R.; Li, W.; Goodell, M.A. DNMT3A loss drives enhancer hypomethylation in FLT3-ITD-associated leukemias. Cancer Cell, 2016, 29(6), 922-934.
[http://dx.doi.org/10.1016/j.ccell.2016.05.003] [PMID: 27300438]
[52]
Wang, L.; Yao, J.; Sun, H.; He, K.; Tong, D.; Song, T.; Huang, C. MicroRNA-101 suppresses progression of lung cancer through the PTEN/AKT signaling pathway by targeting DNA methyltransferase 3A. Oncol. Lett., 2017, 13(1), 329-338.
[http://dx.doi.org/10.3892/ol.2016.5423] [PMID: 28123563]
[53]
Fabbri, M.; Garzon, R.; Cimmino, A.; Liu, Z.; Zanesi, N.; Callegari, E.; Liu, S.; Alder, H.; Costinean, S.; Fernandez-Cymering, C.; Volinia, S.; Guler, G.; Morrison, C.D.; Chan, K.K.; Marcucci, G.; Calin, G.A.; Huebner, K.; Croce, C.M. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc. Natl. Acad. Sci. USA, 2007, 104(40), 15805-15810.
[http://dx.doi.org/10.1073/pnas.0707628104] [PMID: 17890317]
[54]
Viré, E.; Brenner, C.; Deplus, R.; Blanchon, L.; Fraga, M.; Didelot, C.; Morey, L.; Van Eynde, A.; Bernard, D.; Vanderwinden, J.M.; Bollen, M.; Esteller, M.; Di Croce, L.; de Launoit, Y.; Fuks, F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature, 2006, 439(7078), 871-874.
[http://dx.doi.org/10.1038/nature04431] [PMID: 16357870]
[55]
Schlesinger, Y.; Straussman, R.; Keshet, I.; Farkash, S.; Hecht, M.; Zimmerman, J.; Eden, E.; Yakhini, Z.; Ben-Shushan, E.; Reubinoff, B.E.; Bergman, Y.; Simon, I.; Cedar, H. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat. Genet., 2007, 39(2), 232-236.
[http://dx.doi.org/10.1038/ng1950] [PMID: 17200670]
[56]
Jang, K.; Kim, M.; Gilbert, C.A.; Simpkins, F.; Ince, T.A.; Slingerland, J.M. VEGFA activates an epigenetic pathway upregulating ovarian cancer-initiating cells. EMBO Mol. Med., 2017, 9(3), 304-318.
[http://dx.doi.org/10.15252/emmm.201606840] [PMID: 28179359]
[57]
Samowitz, W.S.; Curtin, K.; Ma, K.; Edwards, S.; Schaffer, D.; Leppert, M.F.; Slattery, M.L. Prognostic significance ofp53 mutations in colon cancer at the population level. Int. J. Cancer, 2002, 99(4), 597-602.
[http://dx.doi.org/10.1002/ijc.10405] [PMID: 11992552]
[58]
Wang, Y.A.; Kamarova, Y.; Shen, K.C.; Jiang, Z.; Hahn, M.J.; Wang, Y.; Brooks, S.C. DNA methyltransferase-3a interacts with p53 and represses p53-mediated gene expression. Cancer Biol. Ther., 2005, 4(10), 1138-1143.
[http://dx.doi.org/10.4161/cbt.4.10.2073] [PMID: 16131836]
[59]
Mizuno, S.; Chijiwa, T.; Okamura, T.; Akashi, K.; Fukumaki, Y.; Niho, Y.; Sasaki, H. Expression of DNA methyltransferases DNMT1,3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood, 2001, 97(5), 1172-1179.
[http://dx.doi.org/10.1182/blood.V97.5.1172] [PMID: 11222358]
[60]
Berg, T.; Guo, Y.; Abdelkarim, M.; Fliegauf, M.; Lübbert, M. Reversal of p15/INK4b hypermethylation in AML1/ETO-positive and -negative myeloid leukemia cell lines. Leuk. Res., 2007, 31(4), 497-506.
[http://dx.doi.org/10.1016/j.leukres.2006.08.008] [PMID: 17056112]
[61]
Chan, M.W.; Chan, L.W.; Tang, N.L.; Tong, J.H.; Lo, K.W.; Lee, T.L.; Cheung, H.Y.; Wong, W.S.; Chan, P.S.; Lai, F.M.; To, K.F. Hypermethylation of multiple genes in tumor tissues and voided urine in urinary bladder cancer patients. Clin. Cancer Res., 2002, 8(2), 464-470.
[PMID: 11839665]
[62]
Liang, J.T.; Chang, K.J.; Chen, J.C.; Lee, C.C.; Cheng, Y.M.; Hsu, H.C.; Wu, M.S.; Wang, S.M.; Lin, J.T.; Cheng, A.L. Hypermethylation of the p16 gene in sporadic T3N0M0 stage colorectal cancers: Association with DNA replication error and shorter survival. Oncology, 1999, 57(2), 149-156.
[http://dx.doi.org/10.1159/000012023] [PMID: 10461063]
[63]
Suzuki, M.; Shigematsu, H.; Shames, D.S.; Sunaga, N.; Takahashi, T.; Shivapurkar, N.; Iizasa, T.; Frenkel, E.P.; Minna, J.D.; Fujisawa, T.; Gazdar, A.F. Retraction Note: DNA methylation-associated inactivation of TGFβ-related genes, DRM/Gremlin, RUNX3, and HPP1 in human cancers. Br. J. Cancer, 2013, 109(12), 3132.
[http://dx.doi.org/10.1038/bjc.2013.776] [PMID: 24327071]
[64]
Lu, D.; Ma, Y.; Zhu, A.; Han, Y. An early biomarker and potential therapeutic target of RUNX 3 hypermethylation in breast cancer, a system review and meta-analysis. Oncotarget, 2017, 8(13), 22166-22174.
[http://dx.doi.org/10.18632/oncotarget.13125] [PMID: 27825140]
[65]
Stresemann, C.; Lyko, F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int. J. Cancer, 2008, 123(1), 8-13.
[http://dx.doi.org/10.1002/ijc.23607] [PMID: 18425818]
[66]
Castillo-Aguilera, O.; Depreux, P.; Halby, L.; Arimondo, P.; Goossens, L. DNA methylation targeting: The DNMT/HMT crosstalk challenge. Biomolecules, 2017, 7(4), 3.
[http://dx.doi.org/10.3390/biom7010003] [PMID: 28067760]
[67]
Erdmann, A.; Menon, Y.; Gros, C.; Molinier, N.; Novosad, N.; Samson, A.; Gregoire, J.M.; Long, C.; Ausseil, F.; Halby, L.; Arimondo, P.B. Design and synthesis of new non nucleoside inhibitors of DNMT3A. Bioorg. Med. Chem., 2015, 23(17), 5946-5953.
[http://dx.doi.org/10.1016/j.bmc.2015.06.066] [PMID: 26220519]
[68]
Sergeev, A.; Vorobyov, A.; Yakubovskaya, M.; Kirsanova, O.; Gromova, E. Novel anticancer drug curaxin CBL0137 impairs DNA methylation by eukaryotic DNA methyltransferase Dnmt3a. Bioorg. Med. Chem. Lett., 2020, 30(16), 127296.
[http://dx.doi.org/10.1016/j.bmcl.2020.127296] [PMID: 32631516]
[69]
Shao, Z.; Xu, P.; Xu, W.; Li, L.; Liu, S.; Zhang, R.; Liu, Y.C.; Zhang, C.; Chen, S.; Luo, C. Discovery of novel DNA methyltransferase 3A inhibitors via structure-based virtual screening and biological assays. Bioorg. Med. Chem. Lett., 2017, 27(2), 342-346.
[http://dx.doi.org/10.1016/j.bmcl.2016.11.023] [PMID: 27899265]
[70]
Yu, J.; Chai, X.; Pang, J.; Wang, Z.; Zhao, H.; Xie, T.; Xu, L.; Sheng, R.; Li, D.; Zeng, S.; Hou, T.; Kang, Y. Discovery of novel non-nucleoside inhibitors with high potency and selectivity for DNA methyltransferase 3A. Eur. J. Med. Chem., 2022, 242, 114646.
[http://dx.doi.org/10.1016/j.ejmech.2022.114646] [PMID: 36029561]
[71]
Rilova, E.; Erdmann, A.; Gros, C.; Masson, V.; Aussagues, Y.; Poughon-Cassabois, V.; Rajavelu, A.; Jeltsch, A.; Menon, Y.; Novosad, N.; Gregoire, J.M.; Vispé, S.; Schambel, P.; Ausseil, F.; Sautel, F.; Arimondo, P.B.; Cantagrel, F. Design, synthesis and biological evaluation of 4-amino-N- (4-aminophenyl)benzamide analogues of quinoline-based SGI-1027 as inhibitors of DNA methylation. ChemMedChem, 2014, 9(3), 590-601.
[http://dx.doi.org/10.1002/cmdc.201300420] [PMID: 24678024]
[72]
Valente, S.; Liu, Y.; Schnekenburger, M.; Zwergel, C.; Cosconati, S.; Gros, C.; Tardugno, M.; Labella, D.; Florean, C.; Minden, S.; Hashimoto, H.; Chang, Y.; Zhang, X.; Kirsch, G.; Novellino, E.; Arimondo, P.B.; Miele, E.; Ferretti, E.; Gulino, A.; Diederich, M.; Cheng, X.; Mai, A. Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells. J. Med. Chem., 2014, 57(3), 701-713.
[http://dx.doi.org/10.1021/jm4012627] [PMID: 24387159]
[73]
Erdmann, A.; Menon, Y.; Gros, C.; Masson, V.; Aussagues, Y.; Ausseil, F.; Novosad, N.; Schambel, P.; Baltas, M.; Arimondo, P.B. Identification and optimization of hydrazone-gallate derivatives as specific inhibitors of DNA methyltransferase 3A. Future Med. Chem., 2016, 8(4), 373-380.
[http://dx.doi.org/10.4155/fmc.15.192] [PMID: 26976348]
[74]
Castellano, S.; Kuck, D.; Viviano, M.; Yoo, J.; López-Vallejo, F.; Conti, P.; Tamborini, L.; Pinto, A.; Medina-Franco, J.L.; Sbardella, G. Synthesis and biochemical evaluation of δ(2)-isoxazoline derivatives as DNA methyltransferase 1 inhibitors. J. Med. Chem., 2011, 54(21), 7663-7677.
[http://dx.doi.org/10.1021/jm2010404] [PMID: 21958292]
[75]
Gros, C.; Fleury, L.; Nahoum, V.; Faux, C.; Valente, S.; Labella, D.; Cantagrel, F.; Rilova, E.; Bouhlel, M.A.; David-Cordonnier, M.H.; Dufau, I.; Ausseil, F.; Mai, A.; Mourey, L.; Lacroix, L.; Arimondo, P.B. New insights on the mechanism of quinoline-based DNA Methyltransferase inhibitors. J. Biol. Chem., 2015, 290(10), 6293-6302.
[http://dx.doi.org/10.1074/jbc.M114.594671] [PMID: 25525263]
[76]
Halby, L.; Menon, Y.; Rilova, E.; Pechalrieu, D.; Masson, V.; Faux, C.; Bouhlel, M.A.; David-Cordonnier, M.H.; Novosad, N.; Aussagues, Y.; Samson, A.; Lacroix, L.; Ausseil, F.; Fleury, L.; Guianvarc’h, D.; Ferroud, C.; Arimondo, P.B. Rational design of bisubstrate-type analogues as inhibitors of DNA methyltransferases in cancer Cells. J. Med. Chem., 2017, 60(11), 4665-4679.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00176] [PMID: 28463515]
[77]
Siedlecki, P.; Boy, R.G.; Musch, T.; Brueckner, B.; Suhai, S.; Lyko, F.; Zielenkiewicz, P. Discovery of two novel, small-molecule inhibitors of DNA methylation. J. Med. Chem., 2006, 49(2), 678-683.
[http://dx.doi.org/10.1021/jm050844z] [PMID: 16420053]
[78]
Ceccaldi, A.; Rajavelu, A.; Champion, C.; Rampon, C.; Jurkowska, R.; Jankevicius, G.; Sénamaud-Beaufort, C.; Ponger, L.; Gagey, N.; Dali Ali, H.; Tost, J.; Vriz, S.; Ros, S.; Dauzonne, D.; Jeltsch, A.; Guianvarc’h, D.; Arimondo, P.B. C5-DNA methyltransferase inhibitors: From screening to effects on zebrafish embryo development. ChemBioChem, 2011, 12(9), 1337-1345.
[http://dx.doi.org/10.1002/cbic.201100130] [PMID: 21633996]
[79]
Ceccaldi, A.; Rajavelu, A.; Ragozin, S.; Sénamaud-Beaufort, C.; Bashtrykov, P.; Testa, N.; Dali-Ali, H.; Maulay-Bailly, C.; Amand, S.; Guianvarc’h, D.; Jeltsch, A.; Arimondo, P.B. Identification of novel inhibitors of DNA methylation by screening of a chemical library. ACS Chem. Biol., 2013, 8(3), 543-548.
[http://dx.doi.org/10.1021/cb300565z] [PMID: 23294304]
[80]
Fagan, R.L.; Cryderman, D.E.; Kopelovich, L.; Wallrath, L.L.; Brenner, C. Laccaic acid A is a direct, DNA-competitive inhibitor of DNA methyltransferase 1. J. Biol. Chem., 2013, 288(33), 23858-23867.
[http://dx.doi.org/10.1074/jbc.M113.480517] [PMID: 23839987]
[81]
Kilgore, J.A.; Du, X.; Melito, L.; Wei, S.; Wang, C.; Chin, H.G.; Posner, B.; Pradhan, S.; Ready, J.M.; Williams, N.S. Identification of DNMT1 selective antagonists using a novel scintillation proximity assay. J. Biol. Chem., 2013, 288(27), 19673-19684.
[http://dx.doi.org/10.1074/jbc.M112.443895] [PMID: 23671287]
[82]
Garella, D.; Atlante, S.; Borretto, E.; Cocco, M.; Giorgis, M.; Costale, A.; Stevanato, L.; Miglio, G.; Cencioni, C.; Fernández-de Gortari, E.; Medina-Franco, J.L.; Spallotta, F.; Gaetano, C.; Bertinaria, M. Design and synthesis of N -benzoyl amino acid derivatives as DNA methylation inhibitors. Chem. Biol. Drug Des., 2016, 88(5), 664-676.
[http://dx.doi.org/10.1111/cbdd.12794] [PMID: 27225604]
[83]
Rondelet, G.; Fleury, L.; Faux, C.; Masson, V.; Dubois, J.; Arimondo, P.B.; Willems, L.; Wouters, J. Inhibition studies of DNA methyltransferases by maleimide derivatives of RG108 as non-nucleoside inhibitors. Future Med. Chem., 2017, 9(13), 1465-1481.
[http://dx.doi.org/10.4155/fmc-2017-0074] [PMID: 28795598]
[84]
Saldívar-González, F.I.; Gómez-García, A.; Chávez-Ponce de León, D.E.; Sánchez-Cruz, N.; Ruiz-Rios, J.; Pilón-Jiménez, B.A.; Medina-Franco, J.L. Inhibitors of DNA methyltransferases from natural sources: A computational perspective. Front. Pharmacol., 2018, 9, 1144.
[http://dx.doi.org/10.3389/fphar.2018.01144] [PMID: 30364171]
[85]
San José-Enériz, E.; Agirre, X.; Rabal, O.; Vilas-Zornoza, A.; Sanchez-Arias, J.A.; Miranda, E.; Ugarte, A.; Roa, S.; Paiva, B.; Estella-Hermoso de Mendoza, A.; Alvarez, R.M.; Casares, N.; Segura, V.; Martín-Subero, J.I.; Ogi, F.X.; Soule, P.; Santiveri, C.M.; Campos-Olivas, R.; Castellano, G.; de Barrena, M.G.F.; Rodriguez-Madoz, J.R.; García-Barchino, M.J.; Lasarte, J.J.; Avila, M.A.; Martinez-Climent, J.A.; Oyarzabal, J.; Prosper, F. Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies. Nat. Commun., 2017, 8(1), 15424.
[http://dx.doi.org/10.1038/ncomms15424] [PMID: 28548080]
[86]
Leroy, M.; Mélin, L.; LaPlante, S.R.; Medina-Franco, J.L.; Gagnon, A. Synthesis of NSC 106084 and NSC 14778 and evaluation of their DNMT inhibitory activity. Bioorg. Med. Chem. Lett., 2019, 29(6), 826-831.
[http://dx.doi.org/10.1016/j.bmcl.2019.01.022] [PMID: 30704813]