New Insights on the Mechanism of Quinoline-based DNA Methyltransferase Inhibitors

Summary The process of cytodifferentiation in spermatogenesis is governed by a unique genetic and molecular programme. In this context, accurate ‘tuning’ of the regulatory mechanisms involved in germ cells differentiation is required, as any error could have dramatic consequences on species survival and maintenance. To study the processes that govern the spatial–temporal expression of genes, as well as analyse transmission of epigenetic information to descendants, an integrated approach of genetics, biochemistry and cytology data is necessary. As information in the literature on interplay between DNA methylation and histone H3 lysine 4 trimethylation (H3K4me3) in the advanced stages of murine spermatogenesis is still scarce, we investigated the effect of a DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, at the cytological level using immunocytochemistry methodology. Our results revealed a particular distribution of H3K4me3 during sperm cell differentiation and highlighted an important role for regulation of DNA methylation in controlling histone methylation and chromatin remodelling during spermatogenesis.

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Expanding the Structural Diversity of DNA Methyltransferase Inhibitors

Pharmaceuticals ◽

10.3390/ph14010017 ◽

2020 ◽

Vol 14 (1) ◽

pp. 17

Author(s):

K. Eurídice Juárez-Mercado ◽

Fernando D. Prieto-Martínez ◽

Norberto Sánchez-Cruz ◽

Andrea Peña-Castillo ◽

Diego Prada-Gracia ◽

...

Keyword(s):

Histone Deacetylases ◽

Dna Methyltransferase ◽

Structural Diversity ◽

Dna Methyltransferases ◽

Dna Methyltransferase Inhibitors ◽

Epigenetic Drug ◽

Ic50 Values ◽

Dietary Component ◽

Approved Drugs ◽

Epigenetic Processes

Inhibitors of DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug discovery. They are also chemical tools to understand the biochemistry of epigenetic processes. Herein, we report five distinct inhibitors of DNMT1 characterized in enzymatic inhibition assays that did not show activity with DNMT3B. It was concluded that the dietary component theaflavin is an inhibitor of DNMT1. Two additional novel inhibitors of DNMT1 are the approved drugs glyburide and panobinostat. The DNMT1 enzymatic inhibitory activity of panobinostat, a known pan inhibitor of histone deacetylases, agrees with experimental reports of its ability to reduce DNMT1 activity in liver cancer cell lines. Molecular docking of the active compounds with DNMT1, and re-scoring with the recently developed extended connectivity interaction features approach, led to an excellent agreement between the experimental IC50 values and docking scores.

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Natural Compounds: DNA Methyltransferase Inhibitors in Oral Squamous Cell Carcinoma

Applied Biochemistry and Biotechnology ◽

10.1007/s12010-015-1768-y ◽

2015 ◽

Vol 177 (3) ◽

pp. 577-594 ◽

Cited By ~ 5

Author(s):

Meenakshi Jha ◽

Ruchi Aggarwal ◽

Abhimanyu Kumar Jha ◽

Anju Shrivastava

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Dna Methyltransferase ◽

Natural Compounds ◽

Dna Methyltransferase Inhibitors

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DNA methyltransferase inhibitors increase baculovirus-mediated gene expression in mammalian cells when applied before infection

Analytical Biochemistry ◽

10.1016/j.ab.2009.09.033 ◽

2010 ◽

Vol 396 (2) ◽

pp. 322-324 ◽

Cited By ~ 4

Author(s):

Xin Wang ◽

Juan Yin ◽

Xiaoxia Huang ◽

Jiang Zhong

Keyword(s):

Gene Expression ◽

Mammalian Cells ◽

Dna Methyltransferase ◽

Dna Methyltransferase Inhibitors ◽

Expression In Mammalian Cells

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DNA Methyltransferase Inhibitors

Encyclopedia of Psychopharmacology ◽

10.1007/978-3-540-68706-1_1245 ◽

2010 ◽

pp. 416-416

Author(s):

Nicola Simola ◽

Micaela Morelli ◽

Tooru Mizuno ◽

Suzanne H. Mitchell ◽

Harriet de Wit ◽

...

Keyword(s):

Dna Methyltransferase ◽

Dna Methyltransferase Inhibitors

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Targeting DNA methylation for treating triple-negative breast cancer

Pharmacogenomics ◽

10.2217/pgs-2019-0078 ◽

2019 ◽

Vol 20 (16) ◽

pp. 1151-1157 ◽

Cited By ~ 3

Author(s):

Jia Yu ◽

Jacqueline Zayas ◽

Bo Qin ◽

Liewei Wang

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Tumor Suppressor ◽

Triple Negative Breast Cancer ◽

Targeted Therapies ◽

Tumor Suppressor Genes ◽

Dna Methyltransferase ◽

Triple Negative ◽

Suppressor Genes ◽

Dna Methyltransferase Inhibitors

Triple-negative breast cancer (TNBC) accounts for 15–20% of all invasive breast cancers and tends to have aggressive histological features and poor clinical outcomes. Unlike, estrogen receptor- or HER2-positive diseases, TNBC patients currently lack the US FDA-approved targeted therapies. DNA methylation is a critical mechanism of epigenetic modification. It is well known that aberrant DNA methylation contributes to the malignant transformation of cells by silencing critical tumor suppressor genes. DNA methyltransferase inhibitors reactivate silenced tumor suppressor genes and result in tumor growth arrest, with therapeutic effects observed in patients with hematologic malignancies. The antitumor effect of these DNA methyltransferase inhibitors has also been explored in solid tumors, especially in TNBC that currently lacks targeted therapies.

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