SAR around (l)-S-adenosyl-l-homocysteine, an inhibitor of human DNA methyltransferase (DNMT) enzymes

Saavedra, Oscar M.; Isakovic, Ljubomir; Llewellyn, David B.; Zhan, Lijie; Bernstein, Naomy; Claridge, Stephen; Raeppel, Franck; Vaisburg, A. F.; Elowe, Nadine H.; Petschner, Andrea J.; Rahil, Jubrail; Beaulieu, Norman; MacLeod, A. Robert; Delorme, Daniel; Besterman, Jeffrey M.; Wahhab, Amal

doi:10.1016/j.bmcl.2009.03.113

Cited by 43 publications

(29 citation statements)

References 49 publications

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“…Attachment of small alky or phenyl groups to the N6-position in its adenine base failed to improve its potency against DENV MTase or hRNMT, but moderately enhanced its activity against hDNMT by 2-3-fold. Our findings contradicts a previous report in which compound 3 was found to be inactive against hDNMT (25). Introduction of a benzyl ring retained its activity against DENV MTase and strongly reduced its activity against hRNMT.…”

Section: Discussioncontrasting

confidence: 99%

Small Molecule Inhibitors That Selectively Block Dengue Virus Methyltransferase

Lim

Sonntag

Noble

et al. 2011

Journal of Biological Chemistry

162

183

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Crystal structure analysis of Flavivirus methyltransferases uncovered a flavivirus-conserved cavity located next to the binding site for its cofactor, S-adenosyl-methionine (SAM). Chemical derivatization of S-adenosyl-homocysteine (SAH), the product inhibitor of the methylation reaction, with substituents that extend into the identified cavity, generated inhibitors that showed improved and selective activity against dengue virus methyltransferase (MTase), but not related human enzymes. Crystal structure of dengue virus MTase with a bound SAH derivative revealed that its N6-substituent bound in this cavity and induced conformation changes in residues lining the pocket. These findings demonstrate that one of the major hurdles for the development of methyltransferase-based therapeutics, namely selectivity for disease-related methyltransferases, can be overcome.Methyltransferases (MTases) 3 play key roles in normal physiology and human diseases through methylating DNA, RNA, and proteins. Almost all MTases use S-adenosyl-L-methionine (SAM) as a methyl donor and generate S-adenosyl-Lhomocysteine (SAH) as a by-product. Pharmacological modulation of MTases by small molecules represents a novel approach to therapeutic intervention in cancer and other diseases (1). However, because the core domains of various MTases are conserved, designing inhibitors that specifically block the disease-related MTase without affecting other MTases, has been challenging. The ability to rationally design and generate selective inhibitors would have profound implications for development of new medicines for many methyltransferase-mediated diseases.Dengue virus (DENV), from genus Flavivirus in the family Flaviviridae, is the most prevalent mosquito-borne viral pathogen that infects humans. The four serotypes of DENV (DENV-1 to -4) pose a public health threat to 2.5 billion people worldwide, and cause 50 -100 million human infections each year. Neither vaccine nor antiviral therapy is currently available for DENV. The flavivirus MTase methylates the guanine N7 and ribose 2Ј-O positions of the viral RNA cap in a sequential manner (i.e. GpppA-RNA 3 m7GpppA-RNA 3 m7GpppAm-RNA) (2, 3). Recent studies have shown that flavivirus MTase is critical for viral replication and, therefore, represents a valid target for antiviral therapeutics (4 -6). We therefore examined the feasibility to design inhibitors that specifically modulate flavivirus MTase. EXPERIMENTAL PROCEDURESPreparation of DENV-3 MTases-The DNA fragment representing the MTase domain of DENV-3 was cloned into expression vector pGEX4T1 (Amersham Biosciences). Ala-substitution mutant MTases were prepared using a standard overlapping PCR procedure. Recombinant MTases, containing an N-terminal GST, were expressed in Escherichia coli. BL21 cells and purified through a GSTPrep TM FF 16/10 column (GE Healthcare). The GST tag was then cleaved by thrombin and removed from the MTases using the GST column. The MTases were further purified through gel filtration to ensure protein purity was Ͼ95%. The p...

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Section: Discussioncontrasting

confidence: 99%

Small Molecule Inhibitors That Selectively Block Dengue Virus Methyltransferase

Lim

Sonntag

Noble

et al. 2011

Journal of Biological Chemistry

162

183

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“…Under these conditions, the enzymatic activity of DNMT1 was not affected by nanaomycin A. To our knowledge, this is the first report of a non-SAH (S-adenosyl-L-homocysteine) analogue acting as a DNMT3B-selective inhibitor (34,35).…”

Section: Resultsmentioning

confidence: 74%

Nanaomycin A Selectively Inhibits DNMT3B and Reactivates Silenced Tumor Suppressor Genes in Human Cancer Cells

Kuck

Caulfield

Lyko

et al. 2010

Molecular Cancer Therapeutics

155

116

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Enzymes involved in the epigenetic regulation of the genome represent promising starting points for therapeutic intervention by small molecules, and DNA methyltransferases (DNMT) are emerging targets for the development of a new class of cancer therapeutics. In this work, we present nanaomycin A, initially identified by a virtual screening for inhibitors against DNMT1, as a compound inducing antiproliferative effects in three different tumor cell lines originating from different tissues. Nanaomycin A treatment reduced the global methylation levels in all three cell lines and reactivated transcription of the RASSF1A tumor suppressor gene. In biochemical assays, nanaomycin A revealed selectivity toward DNMT3B. To the best of our knowledge, this is the first DNMT3B-selective inhibitor identified to induce genomic demethylation. Our study thus establishes the possibility of selectively inhibiting individual DNMT enzymes. Mol Cancer Ther; 9(11); 3015-23.

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“…We used the well-known DNMT inhibitor (altough structurally unrelated) S-adenosyl-L-homocysteine (SAH)(54, 55) as the standard which showed IC 50 = 2 μM on DNMT1. For comparison purposes, we also used the parent stilbene resveratrol, which showed inhibition on DNMT3B (IC 50 = 65 μM) and DNMT3A (IC 50 = 105 μM), but no activity on DNMT1 (IC 50 higher than 300 μM, Table 1).…”

Section: Resultsmentioning

confidence: 99%

Resveratrol-salicylate derivatives as selective DNMT3 inhibitors and anticancer agents

Aldawsari

Aguayo‐Ortiz

Kapilashrami

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Resveratrol is a natural polyphenol with plethora of biological activities. Resveratrol has previously shown to decrease DNA methyltransferase (DNMT) enzymes expression and to reactivate silenced tumor suppressor genes. Currently, it seems that no resveratrol analogues have been developed as DNMT inhibitors. Recently, we reported the synthesis of resveratrol-salicylate derivatives and by examining the chemical structure of these analogues, we proposed that these compounds could exhibit DNMT inhibition especially that they resembled NSC 14778, a compound we previously identified as DNMT inhibitor by virtual screening. Indeed, using in vitro DNMT inhibition assay, some of the resveratrol-salicylate analogues we screened in this work showed selective inhibition against DNMT3 enzymes which was greater than resveratrol. A molecular docking study revealed key binding interactions with DNMT3A and DNMT3B enzymes. Additionally, the most active analogues, 10 showed considerable cytotoxicity against three human cancer cells; HT-29, HepG2 and SK-BR-3 which was greater than resveratrol. Further studies are needed to understand the anticancer mechanisms of these derivatives.

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SAR around (l)-S-adenosyl-l-homocysteine, an inhibitor of human DNA methyltransferase (DNMT) enzymes

Cited by 43 publications

References 49 publications

Small Molecule Inhibitors That Selectively Block Dengue Virus Methyltransferase

Small Molecule Inhibitors That Selectively Block Dengue Virus Methyltransferase

Nanaomycin A Selectively Inhibits DNMT3B and Reactivates Silenced Tumor Suppressor Genes in Human Cancer Cells

Resveratrol-salicylate derivatives as selective DNMT3 inhibitors and anticancer agents

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