Identification of DNMT1 Selective Antagonists Using a Novel Scintillation Proximity Assay

Kilgore, Jessica A.; Du, Xiaoqiang; Melito, Lisa; Wei, Shuguang; Wang, Chang-Guang; Chin, Hang Gyeong; Posner, Bruce A.; Pradhan, Sriharsa; Ready, Joseph M.; Williams, Noelle S.

doi:10.1074/jbc.m112.443895

Cited by 43 publications

(41 citation statements)

References 37 publications

(58 reference statements)

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“…As far as we are concerned, our study is the first one reporting the apparent lack of activity of TMS on DNMT1, DNMT3A, and DNMT3B enzymes (Table 1). A similar effect (i.e., loss of enzymatic inhibitory activity with DNMT1 upon methylation of a hydroxyl group), was noted for a sulfonamide DNMT inhibitor recently identified by high-throughput screening (56, 57). …”

Section: Resultssupporting

confidence: 59%

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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Section: Resultssupporting

confidence: 59%

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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“…Indeed, in the screening assay we developed against catalytic Dnmt3A/3L, 94 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 16 intercalators, such as 20 ( Figure 2 and Table 1), are frequent hits found in DNMT screens ( 66,67 and data not shown). 70 To develop DNA ligands as inhibitors of DNA methylation, it is important to keep in mind the need for selectivity towards CpG islands and, ideally, tumor suppressor promoters that are hypermethylated in cancer.…”

Section: / Update On the Identified Inhibitorsmentioning

confidence: 95%

Targeting DNA Methylation with Small Molecules: What’s Next?

et al. 2014

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DNA methylation is a mammalian epigenetic mark that is involved in defining where and when genes are expressed, both in normal cells and in the context of diseases. Like other epigenetic marks, it is reversible and can be modulated by chemical agents. Because it plays an important role in cancer by silencing certain genes, such as tumor suppressor genes, and by reactivating other regions, such as repeated elements, it is a promising therapeutic target. Two compounds are already approved to treat hematological cancers. Many efforts have been carried out to discover new molecules that are able to efficiently inhibit DNA methylation in cancer cells. We will briefly overview the foremost of these efforts by focusing on what we have learned to this point on non-nucleoside inhibitors and on what we consider to be the features of an ideal inhibitor.

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“…The natural quinone antibiotic nanaomycin A ( 43 ) [52,142] and a sulfonamide derivative identified in an HTS, SW155246 ( 44 ) [53,143], have garnered attention as they have shown DNMT inhibition activity and weak but considerable demethylation of promoter regions of specific genes, leading to TSG reactivation. Compound ( 43 ) seems to have other targets and its demethylation activity needs further validation.…”

Section: Inhibition Of Dna Methylation: Other Approachesmentioning

confidence: 99%

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

et al. 2017

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Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each other. Methylation of both DNA and histones is involved in either the activation or silencing of genes and their crosstalk. Since DNA/histone methylation patterns are altered in cancers, molecules that target these modifications are interesting therapeutic tools. We present herein a vast panel of DNA methyltransferase inhibitors classified according to their mechanism, as well as selected histone methyltransferase inhibitors sharing a common mode of action.

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Identification of DNMT1 Selective Antagonists Using a Novel Scintillation Proximity Assay

Cited by 43 publications

References 37 publications

Resveratrol-salicylate derivatives as selective DNMT3 inhibitors and anticancer agents

Resveratrol-salicylate derivatives as selective DNMT3 inhibitors and anticancer agents

Targeting DNA Methylation with Small Molecules: What’s Next?

DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

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