Structure-Guided Optimization of DNA Methyltransferase Inhibitors

Erdmann, Alexandre; Arimondo, Paola B.; Guianvarc’h, Dominique

doi:10.1016/b978-0-12-802808-7.00003-4

Cited by 8 publications

(5 citation statements)

References 88 publications

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“…DNA methylation, the most representative chemical modification in the epigenome, usually occurs in a cytosine-guanine dinucleotide (CpG) site through covalent addition of a methyl group at the 5-carbon position of the cytosine base to form 5-methylcytosine (5mC) ( Skvortsova et al, 2019 ; Wang et al, 2021 ). These CpG sites are not distributed randomly across the human genome, conversely, concentrated in so-called CpG islands situated in gene promoter regions or non-transcribed regions with large repetitive sequences ( Erdmann et al, 2016 ). CpG islands methylation can turn off tumor suppressor genes, which is related to deregulation of the transcriptome and cellular pathways ( Choi et al, 2017 ).…”

Section: Epigenetic Regulation Of Nrf2/keap1 Signaling In Cancermentioning

confidence: 99%

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Epigenetic Therapeutics Targeting NRF2/KEAP1 Signaling in Cancer Oxidative Stress

et al. 2022

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The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) and its negative regulator kelch-like ECH-associated protein 1 (KEAP1) regulate various genes involved in redox homeostasis, which protects cells from stress conditions such as reactive oxygen species and therefore exerts beneficial effects on suppression of carcinogenesis. In addition to their pivotal role in cellular physiology, accumulating innovative studies indicated that NRF2/KEAP1-governed pathways may conversely be oncogenic and cause therapy resistance, which was profoundly modulated by epigenetic mechanism. Therefore, targeting epigenetic regulation in NRF2/KEAP1 signaling is a potential strategy for cancer treatment. In this paper, the current knowledge on the role of NRF2/KEAP1 signaling in cancer oxidative stress is presented, with a focus on how epigenetic modifications might influence cancer initiation and progression. Furthermore, the prospect that epigenetic changes may be used as therapeutic targets for tumor treatment is also investigated.

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Section: Epigenetic Regulation Of Nrf2/keap1 Signaling In Cancermentioning

confidence: 99%

“…Subsequently, the sulfonium methyl of the cofactor SAM transfers to the 5-carbon of the cytosine ring. Afterwards, β-elimination takes place between the 5-carbon and 6-carbon bond to dislodge DNMTs from the methylated cytosine ( Erdmann et al, 2016 ; Poh et al, 2016 ).…”

Section: Epigenetic Regulation Of Nrf2/keap1 Signaling In Cancermentioning

confidence: 99%

Epigenetic Therapeutics Targeting NRF2/KEAP1 Signaling in Cancer Oxidative Stress

et al. 2022

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“…Another strategy worth exploring is to develop protein-protein interaction inhibitors (PPI) for DNMTs. PPIs have been successful for other epigenetic targets, and it is worthwhile since the DNMTs are involved in protein complexes that direct DNA methylation [101,102]. For example, the inhibition of the DNMT1/CFP1 interface with peptides was shown to affect methylation level of cancer cells and to synergize with temozolomide [103].…”

Section: New Approaches To Dnmt Inhibitor Designmentioning

confidence: 99%

Chemical Compounds Targeting DNA Methylation and Hydroxymethylation

Belle

Kawamura

Arimondo

2019

Topics in Medicinal Chemistry

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DNA methylation and its oxidised forms participate in the interpretation and regulation of the human genome. Many questions arise around the enzymes responsible of these chemical modifications of DNA and their roles in regulating these modifications, which are very dynamic but are specific in the location and context (tissues, diseases, etc.). We reviewed here the major enzymes involved in DNA methylation and oxidation, with a focus on the DNA methyltransferases and TET enzymes. The principal compounds that inhibit these enzymes are presented since they will help address these questions.

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“…However, there are structural differences between DNMTs: while DNMT1 relies on its N-terminal domain [15] to recognize hemimethylated strands (hence its function in maintaining the methylation status), DNMT3A and DNMT3B do not show any preference about the methylation status of the DNA, rendering them as de novo transferases. The 3D coordinates of DNMTs with different domains have already been deposited in the Protein Data Bank (PDB) [16]. Based on the structural information, mostly obtained from X-ray crystallography, it is plausible to consider at least three types of inhibitors, namely; (a) molecules binding in the co-factor binding pocket (allosteric inhibition), (b) molecules binding in the DNA binding pocket (competitive inhibition), and (c) molecules interacting directly with the catalytic cysteine (irreversible inhibition).…”

Section: Dnmts: Structure and Mechanismmentioning

confidence: 99%

Progress on the Computational Development of Epigenetic Modulators of DNA Methyltransferases 3A and 3B

2017

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Inhibitors of DNA methyltransferases 3A and 3B (DNMT3A/3B) are promising candidates for the treatment of cancer and other diseases. Selective inhibitors of DNMT3A/3B are also attractive as small-molecule probes. During the past few years has increased significantly the research towards the development of DNMT1 inhibitors. However, there are no reviews of the recent progress in the development of small-molecule inhibitors of DNMT3A/B. Herein we review the status of inhibitors of DNMT3A/3B with emphasis on computational guided approaches. We discuss in a critical manner compound databases containing structure-activity information, crystallographic structures of DNMT3s, structure-guided studies, and virtual (<em>in silico</em>) screening coupled with experimental validation that have led to the identification or development of selective inhibitors. Perspectives in the field are also discussed.

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Structure-Guided Optimization of DNA Methyltransferase Inhibitors

Cited by 8 publications

References 88 publications

Epigenetic Therapeutics Targeting NRF2/KEAP1 Signaling in Cancer Oxidative Stress

Epigenetic Therapeutics Targeting NRF2/KEAP1 Signaling in Cancer Oxidative Stress

Chemical Compounds Targeting DNA Methylation and Hydroxymethylation

Progress on the Computational Development of Epigenetic Modulators of DNA Methyltransferases 3A and 3B

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