DNA methyltransferase inhibitors in cancer: a chemical and therapeutic patent overview and selected clinical studies

Bibliography

• Luger K, Mader AW, Richmond RK, Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 1997;389(6648):251-60
   PubMed Web of Science ®Google Scholar
• Margueron R, Reinberg D. Chromatin structure and the inheritance of epigenetic information. Nat Rev Genet 2010;11(4):285-96
   PubMed Web of Science ®Google Scholar
• Feng S, Jacobsen SE, Reik W. Epigenetic reprogramming in plant and animal development. Science 2010;330(6004):622-7
   PubMed Web of Science ®Google Scholar
• Bonasio R, Tu S, Reinberg D. Molecular signals of epigenetic states. Science 2010;330(6004):612-16
   PubMed Web of Science ®Google Scholar
• Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev 2009;23(7):781-3
   PubMed Web of Science ®Google Scholar
• Bird A. Perceptions of epigenetics. Nature 2007;447(7143):396-8
   PubMed Web of Science ®Google Scholar
• Kouzarides T. Chromatin modifications and their function. Cell 2007;128(4):693-705
   PubMed Web of Science ®Google Scholar
• Mai A, Altucci L. Epi-drugs to fight cancer: from chemistry to cancer treatment, the road ahead. Int J Biochem Cell Biol 2009;41(1):199-213
   PubMed Web of Science ®Google Scholar
• Boumber Y, Issa JP. Epigenetics in cancer: what's the future? Oncology (Williston Park) 2011;25(3):220-6; 8
   Google Scholar
• Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 2007;447(7143):425-32
   PubMed Web of Science ®Google Scholar
• Jurkowska RZ, Jurkowski TP, Jeltsch A. Structure and function of mammalian DNA methyltransferases. ChemBioChem 2011;12(2):206-22
   PubMed Web of Science ®Google Scholar
• Weber M, Hellmann I, Stadler MB, Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 2007;39(4):457-66
   PubMed Web of Science ®Google Scholar
• Ji H, Ehrlich LI, Seita J, Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 2010;467(7313):338-42
   PubMed Web of Science ®Google Scholar
• Doi A, Park IH, Wen B, Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet 2009;41(12):1350-3
   PubMed Web of Science ®Google Scholar
• Irizarry RA, Ladd-Acosta C, Wen B, The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 2009;41(2):178-86
   PubMed Web of Science ®Google Scholar
• Jones PL, Veenstra GJ, Wade PA, Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 1998;19(2):187-91
   PubMed Web of Science ®Google Scholar
• Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2010;31(1):27-36
   PubMed Web of Science ®Google Scholar
• Fournier A, Sasai N, Nakao M, Defossez PA. The role of methyl-binding proteins in chromatin organization and epigenome maintenance. Brief Funct Genomics 2012;11(3):251-64
   PubMed Web of Science ®Google Scholar
• Esteller M. Epigenetics in cancer. N Engl J Med 2008;358(11):1148-59
   PubMed Web of Science ®Google Scholar
• Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet 2006;7(1):21-33
   PubMed Web of Science ®Google Scholar
• Issa JP, Kantarjian HM. Targeting DNA methylation. Clin Cancer Res 2009;15(12):3938-46
   PubMed Web of Science ®Google Scholar
• Constantinides PG, Jones PA, Gevers W. Functional striated muscle cells from non-myoblast precursors following 5-azacytidine treatment. Nature 1977;267(5609):364-6
   PubMed Web of Science ®Google Scholar
• Constantinides PG, Taylor SM, Jones PA. Phenotypic conversion of cultured mouse embryo cells by aza pyrimidine nucleosides. Dev Biol 1978;66(1):57-71
   Google Scholar
• Damaraju VL, Mowles D, Yao S, Role of human nucleoside transporters in the uptake and cytotoxicity of azacitidine and decitabine. Nucleosides Nucleotides Nucleic Acids 2012;31(3):236-55
   PubMed Web of Science ®Google Scholar
• Zhou L, Cheng X, Connolly BA, Zebularine: a novel DNA methylation inhibitor that forms a covalent complex with DNA methyltransferases. J Mol Biol 2002;321(4):591-9
   PubMed Web of Science ®Google Scholar
• National Institute of Health. Inhibitor of DNA methylation. WO2003012051; 2003
   Google Scholar
• National Institute of Health. Methylation inhibitor compounds. WO2005082144; 2005
   Google Scholar
• University of Southern California. N4 modifications of pyrimidine analogs and uses thereof. WO2008054767; 2008
   Google Scholar
• Byun HM, Choi SH, Laird PW, 2'-Deoxy-N4-[2-(4-nitrophenyl)ethoxycarbonyl]-5-azacytidine: a novel inhibitor of DNA methyltransferase that requires activation by human carboxylesterase 1. Cancer Lett 2008;266(2):238-48
   Google Scholar
• Medicine. MSSo. Azacytidine analogues and uses thereof. WO2009042766; 2009
   Google Scholar
• Mount Sinai School of Medicine and Clavis Pharma. Azacytidine analogues and uses thereof. WO2009042767; 2009
   Google Scholar
• Brueckner B, Rius M, Markelova MR, Delivery of 5-azacytidine to human cancer cells by elaidic acid esterification increases therapeutic drug efficacy. Mol Cancer Ther 2010;9(5):1256-64
   PubMed Web of Science ®Google Scholar
• Clavis Pharma second quarter and first half report 2011. Clavis Pharma press release. 2011. Available from: http://www.clavispharma.com/news-events/2011-press-releases/clavis-second-quarter-results-2011 [Last accessed 29 August 2012]
   Google Scholar
• Marquez VE, Lim MI, Treanor SP, Cyclopentenylcytosine. A carboxylic nucleoside with antitumor and antiviral properties. J Med Chem 1988;31:1987-94
   Google Scholar
• Rexan Corporation. Nucleoside derivatives and therapeutic use thereof. WO2005097757; 2005
   Google Scholar
• Choi WJ, Chung HJ, Chandra G, Fluorocyclopentenyl-cytosine with broad spectrum and potent antitumor activity. J Med Chem 2012;55(9):4521-5
   PubMed Web of Science ®Google Scholar
• Peters G, Smid K, Vecchi L, Abstract 1770: Metabolism and mechanism of action of fluorocyclopentenylcytosine (RX-3117). Proceedings: AACR 103rd Annual Meeting 2012. Cancer Res 2012;72:8 Suppl 1. doi: 10.1158/1538-7445.AM2012-1770
   Google Scholar
• Rexahn Pharmaceuticals Enrolls First Subject in Exploratory Phase I Clinical Study of RX-3117. Rexahn press release. 2012. Available from: http://www.rexahn.com/cms/index.php/2012/03/rexahn-pharmaceuticals-enrolls-first-subject-in-exploratory-phase-i-clinical-study-of-rx-3117/ [Last accessed 22 June 2012]
   Google Scholar
• Instytut Chemii Bioorganicznej PAN. A cytosine analogue, a method of preparation of a cytosine analogue, a DNA methyltransferase 1 inhibitor, a method for DNA methylation inhibition, the use of the analogue in the treatment of diseases associated with deviations from normal DNA methylation. WO2011115513; 2011
   Google Scholar
• Instytut Chemii Bioorganicznej PAN. Method of obtaining of 4-furfurylcytosine and/or its derivatives, an anti-aging composition and use of 4-furfurylcytosine and/or its derivatives in the manufacture of anti-aging composition. WO2009067035; 2009
   Google Scholar
• Southern Research Institute. The use of 2’-deoxy-4’-thiocytidine and its analogues as DNA hypomethylating anticancer agents. WO2011109012; 2009
   Google Scholar
• SuperGen. Oligonucleotide analogues incorporating 5-aza-cytosine therein. WO2007041071; 2007
   Google Scholar
• Chuang JC, Warner SL, Vollmer D, S110, a 5-Aza-2'-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther 2010;9(5):1443-50
   PubMed Web of Science ®Google Scholar
• Yoo CB, Jeong S, Egger G, Delivery of 5-aza-2'-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res 2007;67(13):6400-8
   PubMed Web of Science ®Google Scholar
• A phase 1-2, dose escalation, multicenter study of two subcutaneous regimens of SGI-110, a DNA hypomethylating agent, in subjects with intermediate or high-risk myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML). NCT01261312. ClinicalTrials.gov. 2010. Available from: http://clinicaltrials.gov/ct2/show/NCT01261312?term=NCT01261312&rank=1 [Last accessed 20 July 2012]
   Google Scholar
• Methylgene. Inhibitors of DNA methyltransferase. WO2006078752; 2006
   Google Scholar
• SuperGen. Quinoline derivatives for modulating DNA methylation. WO2009049132; 2009
   Google Scholar
• Denny WA, Atwell GJ, Baguley BC, Cain BF. Potential antitumor agents. 29. Quantitative structure-activity relationships for the antileukemic bisquaternary ammonium heterocycles. J Med Chem 1979;22(2):134-50
   Google Scholar
• Datta J, Ghoshal K, Denny WA, A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation. Cancer Res 2009;69(10):4277-85
   PubMed Web of Science ®Google Scholar
• Foundation. UoLR. Therapeutic compounds. WO2008098077; 2008
   Google Scholar
• Andrianasolo EH, France D, Cornell-Kennon S, Gerwick WH. DNA methyl transferase inhibiting halogenated monoterpenes from the Madagascar red marine alga Portieria hornemannii. J Nat Prod 2006;69(4):576-9
   Google Scholar
• SuperGen. Cyclopentathiophene/cyclohexathiophene DNA methyltransferase inhibitors. WO2010098866; 2010
   Google Scholar
• DKFZ. Inhibitors of DNA methylation in tumor cells. EP1574449; 2005
   Google Scholar
• Siedlecki P, Boy RG, Musch T, Discovery of two novel, small-molecule inhibitors of DNA methylation. J Med Chem 2006;49(2):678-83
   PubMed Web of Science ®Google Scholar
• Brueckner B, Garcia Boy R, Siedlecki P, Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Res 2005;65(14):6305-11
   PubMed Web of Science ®Google Scholar
• Cancer Research Technology Ltd. Phthalimides, succinimides and related compounds and their use as pharmaceuticals. WO2007007054; 2007
   Google Scholar
• Curis, Inc. DNA methyl transferase inhibitors containing a zinc binding moiety. WO2008033744; 2008
   Google Scholar
• Suzuki T, Tanaka R, Hamada S, Design, synthesis, inhibitory activity, and binding mode study of novel DNA methyltransferase 1 inhibitors. Bioorg Med Chem Lett 2010;20(3):1124-7
   PubMed Web of Science ®Google Scholar
• Halby L, Champion C, Senamaud-Beaufort C, Rapid synthesis of new DNMT inhibitors derivatives of procainamide. ChemBioChem 2012;13(1):157-65
   PubMed Web of Science ®Google Scholar
• Cornacchia E, Golbus J, Maybaum J, Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. J Immunol 1988;140(7):2197-200
   PubMed Web of Science ®Google Scholar
• Universidad Nacional Autonoma de Mexico. Hydralazine and procainamide use in cancer treatment as reactivators of the expression of tumor suppressor genes. 2002
   Google Scholar
• Villar-Garea A, Fraga MF, Espada J, Esteller M. Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. Cancer Res 2003;63(16):4984-9
   PubMed Web of Science ®Google Scholar
• INSERM. Substituted aminobenzoic acid derivatives as inhibitors of DNA methyltransferases. WO2012038417; 2012
   Google Scholar
• Ohio State University Research Foundation. DNA methylation inhibitors. WO2012087889; 2012
   Google Scholar
• Lin YS, Shaw AY, Wang SG, Identification of novel DNA methylation inhibitors via a two-component reporter gene system. J Biomed Sci 2011;18:3
   Google Scholar
• Fang MZ, Chen D, Sun Y, Reversal of hypermethylation and reactivation of p16INK4a, RARbeta, and MGMT genes by genistein and other isoflavones from soy. Clin Cancer Res 2005;11(19 Pt 1):7033-41
   PubMed Web of Science ®Google Scholar
• INSERM. Flavones and flavanones derivatives as DNA methyltransferases inhibitors. WO2011029956; 2011
   Google Scholar
• Dauzonne D, Folleas B, Martinez L, Chabot G. Synthesis and in vitro cytotoxicity of a series of 3-aminoflavones. Eur J Med Chem 1997;32(1):71-82
   Google Scholar
• Gonzalez De Peredo A, Leonce S, Monneret C, Dauzonne D. Synthesis and biological evaluation of flavanones and flavones related to podophyllotoxin. Chem Pharm Bull (Tokyo) 1998;46(1):79-83
   Google Scholar
• Bauvois B, Puiffe ML, Bongui JB, Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13. J Med Chem 2003;46(18):3900-13
   Google Scholar
• Liu Z, Xie Z, Jones W, Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett 2009;19(3):706-9
   PubMed Web of Science ®Google Scholar
• Ohio State University. Curcumin compositions and uses thereof. WO2012024405; 2012
   Google Scholar
• Pina IC, Gautschi JT, Wang GY, Psammaplins from the sponge Pseudoceratina purpurea: inhibition of both histone deacetylase and DNA methyltransferase. J Org Chem 2003;68(10):3866-73
   PubMed Web of Science ®Google Scholar
• CNRS. Novel derivatives of psammaplin A, a method for their synthesis and their use for the prevention and treatment of cancer. WO2008125988; 2008
   Google Scholar
• Baud MG, Leiser T, Haus P, Defining the mechanism of action and enzymatic selectivity of psammaplin A against its epigenetic targets. J Med Chem 2012;55(4):1731-50
   PubMed Web of Science ®Google Scholar
• Jacobs University Bremen. Method and reagents for analyzing nucleic acid methylation reactions. PCTEP2008003779; 2008
   Google Scholar
• Methylgene news release. 2006. Available from: http://sedar.com/GetFile.do?lang=EN&docClass=8&issuerNo=00020670&fileName=/csfsprod/data75/filings/01031676/00000001/s%3A%5Czzzseb%5Cmeta1215.pdf [Last accessed 29 August 2012]
   Google Scholar
• Plummer R, Vidal L, Griffin M, Phase I study of MG98, an oligonucleotide antisense inhibitor of human DNA methyltransferase 1, given as a 7-day infusion in patients with advanced solid tumors. Clin Cancer Res 2009;15(9):3177-83
   PubMed Web of Science ®Google Scholar
• Arce C, Segura-Pacheco B, Perez-Cardenas E, Hydralazine target: from blood vessels to the epigenome. J Transl Med 2006;4:10
   PubMed Web of Science ®Google Scholar
• Psicofarma SA. Pharmaceutical composition for the sustained release of hydralazine and use thereof as a support for cancer treatment. 2009
   Google Scholar
• Lin J, Haffner MC, Zhang Y, Disulfiram is a DNA demethylating agent and inhibits prostate cancer cell growth. Prostate 2011;71(4):333-43
   PubMed Web of Science ®Google Scholar
• Study of recurrent prostate cancer with rising prostate specific antigen (PSA) (NCT01118741).. ClinicalTrials.gov. 2010. Available from: http://clinicaltrials.gov/ct2/show/NCT01118741?term=dna+methyltransferase&rank=6 [Last accessed 18 July 2012]
   Google Scholar
• 5-Fluoro-2'-deoxycytidine and tetrahydrouridine to treat patients with advanced cancer (NCT00359606). ClinicalTrials.gov. 2006. Available from: http://clinicaltrials.gov/ct2/show/NCT00359606?term=dna+methyltransferase&rank=25 [Last accessed 18 July 2012]
   Google Scholar
• FdCyd and THU for advanced solid tumors (NCT01534598). ClinicalTrials.gov. 2012. Available from: http://clinicaltrials.gov/ct2/show/NCT01534598?term=dna+methyltransferase&rank=26 [Last accessed 18 July 2012]
   Google Scholar
• A multi-histology phase II study of 5-fluoro-2-deoxycytidine with tetrahydrouridine (FdCyd + THU) (NCT00978250). ClinicalTrials.gov. 2009. Available from: http://clinicaltrials.gov/ct2/show/NCT00978250?term=dna+methyltransferase&rank=23 [Last accessed 18 July 2012]
   Google Scholar
• A phase 2, randomized, open-label study of azacitidine (Vidaza) vs MGCD0103 vs azacitidine in combination with MGCD0103 for the treatment of elderly subjects with newly diagnosed AML or intermediate-2 or high-risk MDS(NCT00666497). ClinicalTrials.gov. 2008. Available from: http://clinicaltrials.gov/ct2/show/NCT00666497?term=dna+methyltransferase&rank=5 [Last accessed 18 July 2012]
   Google Scholar
• Juergens RA, Wrangle J, Vendetti FP, Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov 2011;1(7):598-607
   PubMed Web of Science ®Google Scholar
• Randomized phase II trial of adjuvant combined epigenetic therapy with azacitidine and entinostat in resected stage I Non-small Cell Lung Cancer versus standard care (NCT01207726). ClinicalTrials.gov. 2010. Available from: http://clinicaltrials.gov/ct2/show/NCT01207726?term=dna+methyltransferase&rank=17 [Last accessed 18 July 2012]
   Google Scholar
• A phase I study of oral azacitidine as a single agent and in combination with carboplatin or ABI-007 in subjects with relapsed or refractory solid tumors (NCT01478685). ClinicalTrials.gov. 2011. Available from: http://clinicaltrials.gov/ct2/show/NCT01478685?term=dnmt&rank=7 [Last accessed 18 July 2012]
   Google Scholar
• Induction therapy with decitabine and plerixafor priming for patients ≥ 60 years with Acute Myeloid Leukemia (NCT01352650). ClinicalTrials.gov. 2011. Available from: http://clinicaltrials.gov/ct2/show/NCT01352650?term=dna+methyltransferase&rank=7 [Last accessed 18 July 2012]
   Google Scholar
• Targeted demethylation to enhance response or overcome resistance to EGFR blocking agents in KRAS wild-type metastatic colorectal cancer patients using sequential decitabine and panitumumab (NCT00879385). ClinicalTrials.gov. 2009. Available from: http://clinicaltrials.gov/ct2/show/NCT00879385?term=dna+methyltransferase&rank=3 [Last accessed 18 July 2012]
   Google Scholar
• A proof of concept study of non-DNA damaging DNMT1 depletion therapy for myelodysplastic syndrome (NCT01165996). ClinicalTrials.gov. 2010. Available from: http://clinicaltrials.gov/ct2/show/NCT01165996?term=dnmt&rank=2 [Last accessed 18 July 2012]
   Google Scholar
• Inhibition of DNA methylation by 1-hr infusion of 5-aza-2'-deoxycitidine (decitabine) x 10 days (M-F) with escalating doses of SC pegylated (PEG) Interferon-alfa 2B: a phase I study with molecular correlates (NCT00701298). ClinicalTrials.gov. 2008. Available from: http://clinicaltrials.gov/ct2/show/NCT00701298?term=dnmt&rank=10 [Last accessed 18 July 2012]
   Google Scholar
• Phase I/II Trial of tamoxifen following epigenetic regeneration of estrogen receptor using decitabine and LBH 589 in patients with triple negative metastatic breast cancer (NCT01194908). ClinicalTrials.gov. 2008. Available from: http://clinicaltrials.gov/ct2/show/NCT01194908?term=epigenetic+AND+cancer&rank=15 [Last accessed 19 July 2012]
   Google Scholar
• Jia D, Jurkowska RZ, Zhang X, Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 2007;449(7159):248-51
   PubMed Web of Science ®Google Scholar
• Song J, Rechkoblit O, Bestor TH, Patel DJ. Structure of DNMT1-DNA complex reveals a role for autoinhibition in maintenance DNA methylation. Science 2011;331(6020):1036-40
   PubMed Web of Science ®Google Scholar
• Song J, Teplova M, Ishibe-Murakami S, Patel DJ. Structure-based mechanistic insights into DNMT1-mediated maintenance DNA methylation. Science 2012;335(6069):709-12
   PubMed Web of Science ®Google Scholar