ACS Medicinal Chemistry Letters
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Git, A.; Spiteri, I.; Das, P. P.; Caldas, C.; Miska, E.; Esteller, M. Genetic
unmasking of an epigenetically silenced microRNA in human
cancer cells. Cancer Res. 2007, 67, 1424-1429.
nanaomycin A and RG108. Initial exploration of analogues of
11 led to synthesis of 17 new compounds in three series. The
activity of the most potent compound 33h was confirmed in an
additional ultra-high-performance liquid chromatography
(UHPLC)-based analytical assay. The SAR data was found to
be consistent with computed structures for the complexes of the
small molecules with DNMT3B.
(8) Yaqinuddin, A.; Qureshi, S. A.; Qazi, R.; Abbas, F. Down-
regulation of DNMT3b in PC3 cells effects locus-specific DNA
methylation, and represses cellular growth and migration. Cancer
Cell Int. 2008, 8, 13.
(9) Gros, C.; Fahy, J.; Halby, L.; Dufau, I.; Erdmann, A.; Gregorie,
J. M.; Ausseil F.; Vispé, S.; Arimondo, P. B. DNA methylation
inhibitors in cancer: recent and future approaches. Biochimie
2012, 94, 2280-2296.
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(10) Xu, F.; Mao, C.; Ding, Y.; Rui, C.; Wu, L.; Shi, A.; Zhang, H.;
Zhang, L.; Xu, Z. Molecular and enzymatic profiles of mammalian
DNA methyltransferases: structures and targets for drugs. Curr.
Med. Chem. 2010, 17, 4052-4071.
(11) Kuck, D.; Singh, N.; Lyko, F.; Medina-Franco, J. L. Novel and
selective DNA methyltransferase inhibitors: Docking-based virtual
screening and experimental evaluation. Bioorg. Med. Chem. 2010,
18, 822-829.
(12) Beaulieu, N.; Morin, S.; Chute, I. C.; Robert, M. F.; Nguyen, H.;
Macleod, A. R. An essential role for DNA methyltransferase
DNMT3B in cancer cell survival. J. Biol. Chem. 2002, 277, 28176-
28181.
(13) Kuck, D.; Caulfield, T.; Lyko, F.; Medina-Franco, J. L
Nanaomycin A selectively inhibitors DNMT3B and reactivates
silenced tumor suppressor genes in human cancer cells. Mol.
Cancer Ther. 2010, 9, 3015-3023.
(14) Hagemann, S.; Kuck, D.; Stresemann, C.; Prinz, F,;
Brueckner, B; Mund, C.; Mumberg, D,; Sommer, A. Antirpoliferative
effects of DNA methyltransferase 3B depletion are not associated
with DNA demethylation. PLoS One 2012, 7, e36125.
(15) Micevic, G.; Muthusamy, V.; Damsky, W.; Theodosakis, N.;
Liu, X.; Meeth, K.; Wingrove, E.; Santhanakrishnan, M.; Bosenberg,
M. DNMT3b modulates melanoma growth by controlling levels of
mTORC2 component RICTOR. Cell. Rep. 2016, 14, 2180-2192.
(16) Caulfield, T.; Medina-Franco, J. L. Molecular dynamics
simulations of human DNA methyltransferase 3B with selective
inhibitor nanaomycin A. J. Struct. Biol. 2011, 176, 185-191.
(17) Prime v3.0; Schrödinger, LLC: New York, NY, 2011.
(18) Jia, D.; Jurkowska, R. Z.; Zhang, X.; Jeltsch, A.; Cheng, X.
Structure of DNMT3a bound to DMLT3L suggests a model for de
novo DNA methylation. Nature 2007, 449, 248-251.
(19) Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.;
Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.;
Perry, J. K.; Shaw, D. E.; Francis, P.; Shenkin, P. S. Glide: anew
approach for rapid, accurate docking and scoring. 1. Method and
assessment of docking accuracy. J. Med. Chem. 2004, 47, 1739-
1749.
Supporting Information. Experimental details for the
constructed homology-model, virtual screening and in vitro
characterization of DNMT activity. Full synthetic procedures
and spectral characterization data for all intermediates and
final compounds. A PDB coordinate file for the complex of 33h
and DNMT3B. This information is available free of charge via
AUTHOR INFORMATION
Corresponding Authors
* william.jorgensen@yale.edu
Notes
The authors declare no competing interests.
ACKNOWLEDGMENT
Gratitude is expressed to the National Institutes of Health
(GM32136) and Melanoma Research Alliance for support,
“Epigenetics in Melanoma: Mechanistic Evaluation on Novel
Therapies”. This work is dedicated to the memory of Prof.
Maurizio Botta with gratitude for his spirit, inspiration, and
encouragement.
ABBREVIATIONS
DNMT, DNA Methyltransferase; DNA, Deoxyribonucleic acid;
RNA, ribonucleic acid; miRNA, MicroRNAs; SAM, S-adenosyl
methionine; HATU, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-
triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; DIPEA,
N,
N-Diisopropylethylamine;
PyBOP,
benzotriazol-1-yl-
oxytripyrrolidinophosphonium hexafluorophosphate.
REFERENCES
(1) Sharma, S.; Kelly, T.K.: Jonas, P. A. Epigenetics in cancer.
Carcinogenesis. 2010, 31, 27-36.
(2) Jurkowska, R. Z.; Jurkowski, T. P.; Jeltsch, A. Structure and
function of mammalian DNA methyltransferases. Chembiochem
2011, 12, 206-222.
(3) Song, J.; Rechkoblit, O.; Bestor, T. H.; Patel, D. J. Structure of
DNMT1-DNA complex reveals a role for autoinhibition in
maintenance DNA methylation. Science 2011, 331, 1036-1040.
(4) 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,
2291-2298.
(5) Jones, P. A. Functions of DNA methylation: islands, start sites,
gene bodies and beyond. Nat. Rev. Genet. 2012, 13, 484-492.
(6) Esteller, M. CpG island hypermethylation and tumor
suppressor genes: a booming present, a brighter future. Oncongene
2002, 21, 5427-5440.
(20) Irwin, J. J.; Shoichet, B. K. ZINC—a free database of
commercially available compounds for virtual screening. J. Chem.
Inf. Model 2005, 45, 177-182.
(21) Jones, G.; Willett, P.; Glen, R. C.; Glen, R. C.; Leach, A. R.;
Taylor, R. Development and validation of a genetic algorithm for
flexible docking. J. Mol. Biol. 1997, 267, 727-748.
(22) Friesner, R. A.; Murphy, R. B.; Repasky, M. P.; Frye, L. L.;
Greenwood, J. R.; Halgren, T. A.; Sanschagrin, P. C.; Mainz, D. T.
Extra precision glide: docking and scoring incorporating a model
of hydrophobic enclosure for protein-ligand complexes. J. Med.
Chem. 2006, 49, 6177-6196.
(23) Wood, R. J.; McKelvie, J. C.; Maynard-Smith, M. D.; Roach, P.
L. A real-time assay for CpG-specific cytosine-C5 methyltransferase
activity. Nucleic Acids Res. 2010, 38, e107.
(24) Jorgensen, W. L. Efficient Drug Lead Discovery and
Optimization. Acc. Chem. Res. 2009, 42, 724-733.
(25) Sasaki, T.; Kudalkar, S. N.; Bertoletti, N.; Anderson, K.
DRONE: Direct Tracking of DNA Cytidine Deamination and Other
DNA Modifying Activities. Anal. Chem. 2018, 90, 11735-1174.
(7) Lujambio, A.; Ropero, S.; Ballestar, E.; Fraga, M. F.; Cerrato,
C.; Setién, F.; Casado, S.; Suarez-Gauthier, A.; Sanchez-Cespedes, M.;
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