| Reference | 1. J Med Chem. 2014 Jan 23;57(2):421-34. doi: 10.1021/jm401419p. Epub 2014 Jan 9.
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Synthesis and evaluation of analogues of N-phthaloyl-l-tryptophan (RG108) as
inhibitors of DNA methyltransferase 1.
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Asgatay S(1), Champion C, Marloie G, Drujon T, Senamaud-Beaufort C, Ceccaldi A,
Erdmann A, Rajavelu A, Schambel P, Jeltsch A, Lequin O, Karoyan P, Arimondo PB,
Guianvarc/’h D.
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Author information: <br>
(1)Laboratoire des BioMolécules, UMR 7203, Université Pierre et Marie Curie-Paris
6, ENS, CNRS, 4, Place Jussieu, 75252 Paris Cedex 05, France.
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DNA methyltransferases (DNMT) are promising drug targets in cancer provided that
new, more specific, and chemically stable inhibitors are discovered. Among the
non-nucleoside DNMT inhibitors, N-phthaloyl-l-tryptophan 1 (RG108) was first
identified as inhibitor of DNMT1. Here, 1 analogues were synthesized to
understand its interaction with DNMT. The indole, carboxylate, and phthalimide
moieties were modified. Homologated and conformationally constrained analogues
were prepared. The latter were synthesized from prolinohomotryptophan derivatives
through a methodology based amino-zinc-ene-enolate cyclization. All compounds
were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained
compounds 16-18 and NPys derivatives 10-11 were found to be at least 10-fold more
potent than the reference compound. The cytotoxicity on the tumor DU145 cell line
of the most potent inhibitors was correlated to their inhibitory potency.
Finally, docking studies were conducted in order to understand their binding
mode. This study provides insights for the design of the next-generation of DNMT
inhibitors.
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2. Cell Biol Int. 2012 Nov 1;36(11):1067-78. doi: 10.1042/CBI20110649.
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DNA methyltransferase inhibitor RG108 and histone deacetylase inhibitors
cooperate to enhance NB4 cell differentiation and E-cadherin re-expression by
chromatin remodelling.
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Savickiene J(1), Treigyte G, Jazdauskaite A, Borutinskaite VV, Navakauskiene R.
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Author information: <br>
(1)Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius
University, Mokslininku Street 12, LT08662, Vilnius, Lithuania.
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Epigenetic silencing of cancer-related genes by abnormal methylation and the
reversal of this process by DNA methylation inhibitors represents a promising
strategy in cancer therapy. As DNA methylation affects gene expression and
chromatin structure, we investigated the effects of novel DNMT (DNA
methyltransferase) inhibitor, RG108, alone and in its combinations with
structurally several HDAC (histone deacetylase) inhibitors [sodium PB (phenyl
butyrate) or BML-210 (N-(2-aminophenyl)-N/’phenyloctanol diamine), and all-trans
RA (retinoic acid)] in the human PML (promyelocytic leukaemia) NB4 cells. RG108
at different doses from 20 to 100 μM caused time-, but not a dose-dependent
inhibition of NB4 cell proliferation without cytotoxicity. Temporal pretreatment
with RG108 before RA resulted in a dose-dependent cell growth inhibition and
remarkable acceleration of granulocytic differentiation. Prolonged treatments
with RG108 and RA in the presence of HDAC inhibitors significantly increased
differentiation. RG108 caused time-dependent re-expression of
methylation-silenced E-cadherin, with increase after temporal or continuous
treatments with RG108 and RA, or RA together with PB in parallel, in cell
maturation, suggesting the role of E-cadherin as a possible therapeutic marker.
These processes required both PB-induced hyperacetylation of histone H4 and
trimethylation of histone H3 at lysine 4, indicating the cooperative action of
histone modifications and DNA methylation/demethylation in derepression of
E-cadherin. This work provides novel experimental evidence of the beneficial role
of the DNMT inhibitor RG108 in combinations with RA and HDACIs in the effective
differentiation of human PML based on epigenetics.
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3. Bioconjug Chem. 2006 Mar-Apr;17(2):261-6.
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Synthesis and in vitro evaluation of biotinylated RG108: a high affinity compound
for studying binding interactions with human DNA methyltransferases.
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Schirrmacher E(1), Beck C, Brueckner B, Schmitges F, Siedlecki P, Bartenstein P,
Lyko F, Schirrmacher R.
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Author information: <br>
(1)Division of Epigenetics, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld
580, 69120 Heidelberg, Germany. [email protected]
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Small-molecule inhibitors of DNA methyltransferases such as RG108 represent
promising candidates for cancer drug development. We report the synthesis and in
vitro analysis of a biotinylated RG108 conjugate,
2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(5-[3-[5-(2-oxo-hexahydro-thieno[3,4-d]
imidazol-4-yl)pentanoylamino]propoxy]-1H-indol-3-yl)propionic acid (bio-RG108),
for the evaluation of interactions with DNA methyltransferase enzymes. The
structural design of the chemically modified inhibitor was aided by molecular
modeling, which suggested the possibility for extensive chemical modifications at
the 5-position of the tryptophan moiety in RG108. The inhibitory activity of the
corresponding derivative was confirmed in a cell-free biochemical assay, where
bio-RG108 showed an undiminished inhibition of DNA methyltransferase activity
(IC50 = 40 nM). Bio-RG108 therefore represents a suitable bioconjugate for the
elucidation of inhibitory mechanisms and for the affinity purification of
RG108-associated proteins.
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