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Modulators of Histone Methylation: A Medicinal Chemistry Perspective

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (1 June 2018) | Viewed by 14473

Special Issue Editors


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Guest Editor
Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
Interests: epigenetics; HDACs; SIRTs; DNMTs; drug design
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Epigenetics include all chromatin modifications occurring on both histones and DNA without affecting gene sequence (genetic). Several proteins are involved in these processes, and have been grouped into writers (i.e., HAT and HMT), readers (bromodomain and cromodomain) and erasers (HDAC, KDM), which play an important and precise role in controlling gene expression and cell functions. Histone methyl transferases, demethylases, as well as methyl readers, represent innovative and modern targets to develop potential new drugs useful for future treatment of several diseases, including cancer, metabolic disorders, inflammation and neurodegeneration.

This Special Issue aims to highlight recent research efforts on the medicinal chemistry approaches on histone methylation modulators and pointing a special attention to innovative medicinal chemistry and chemical biology recently applied to identifying new ligands as new potent and selective epigenetic modulators and their therapeutic potential.

We welcome original articles and short communications, as well as a limited number of review articles, on novel modulators of protein targets involved in histone methylation. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Dr. Sergio Valente
Prof. Dr. Rino Ragno

Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • epigenetics
  • histones
  • chromatin modifiers
  • methylation
  • cromodomain
  • cancer

Published Papers (3 papers)

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Research

19 pages, 3812 KiB  
Article
Small Molecule Inhibitors of KDM5 Histone Demethylases Increase the Radiosensitivity of Breast Cancer Cells Overexpressing JARID1B
by Simone Pippa, Cecilia Mannironi, Valerio Licursi, Luca Bombardi, Gianni Colotti, Enrico Cundari, Adriano Mollica, Antonio Coluccia, Valentina Naccarato, Giuseppe La Regina, Romano Silvestri and Rodolfo Negri
Molecules 2019, 24(9), 1739; https://doi.org/10.3390/molecules24091739 - 4 May 2019
Cited by 23 | Viewed by 4483
Abstract
Background: KDM5 enzymes are H3K4 specific histone demethylases involved in transcriptional regulation and DNA repair. These proteins are overexpressed in different kinds of cancer, including breast, prostate and bladder carcinomas, with positive effects on cancer proliferation and chemoresistance. For these reasons, these [...] Read more.
Background: KDM5 enzymes are H3K4 specific histone demethylases involved in transcriptional regulation and DNA repair. These proteins are overexpressed in different kinds of cancer, including breast, prostate and bladder carcinomas, with positive effects on cancer proliferation and chemoresistance. For these reasons, these enzymes are potential therapeutic targets. Methods: In the present study, we analyzed the effects of three different inhibitors of KDM5 enzymes in MCF-7 breast cancer cells over-expressing one of them, namely KDM5B/JARID1B. In particular we tested H3K4 demethylation (western blot); radio-sensitivity (cytoxicity and clonogenic assays) and damage accumulation (COMET assay and kinetics of H2AX phosphorylation). Results: we show that all three compounds with completely different chemical structures can selectively inhibit KDM5 enzymes and are capable of increasing sensitivity of breast cancer cells to ionizing radiation and radiation-induced damage. Conclusions: These findings confirm the involvement of H3K4 specific demethylases in the response to DNA damage, show a requirement of the catalytic function and suggest new strategies for the therapeutic use of their inhibitors. Full article
(This article belongs to the Special Issue Modulators of Histone Methylation: A Medicinal Chemistry Perspective)
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9 pages, 930 KiB  
Article
Crystal Structure of LSD1 in Complex with 4-[5-(Piperidin-4-ylmethoxy)-2-(p-tolyl)pyridin-3-yl]benzonitrile
by Hideaki Niwa, Shin Sato, Tomoko Hashimoto, Kenji Matsuno and Takashi Umehara
Molecules 2018, 23(7), 1538; https://doi.org/10.3390/molecules23071538 - 26 Jun 2018
Cited by 21 | Viewed by 4704
Abstract
Because lysine-specific demethylase 1 (LSD1) regulates the maintenance of cancer stem cell properties, small-molecule inhibitors of LSD1 are expected to be useful for the treatment of several cancers. Reversible inhibitors of LSD1 with submicromolar inhibitory potency have recently been reported, but their exact [...] Read more.
Because lysine-specific demethylase 1 (LSD1) regulates the maintenance of cancer stem cell properties, small-molecule inhibitors of LSD1 are expected to be useful for the treatment of several cancers. Reversible inhibitors of LSD1 with submicromolar inhibitory potency have recently been reported, but their exact binding modes are poorly understood. In this study, we synthesized a recently reported reversible inhibitor, 4-[5-(piperidin-4-ylmethoxy)-2-(p-tolyl)pyridin-3-yl]benzonitrile, which bears a 4-piperidinylmethoxy group, a 4-methylphenyl group, and a 4-cyanophenyl group on a pyridine ring, and determined the crystal structure of LSD1 in complex with this inhibitor at 2.96 Å. We observed strong electron density for the compound, showing that its cyano group forms a hydrogen bond with Lys661, which is a critical residue in the lysine demethylation reaction located deep in the catalytic center of LSD1. The piperidine ring interacts with the side chains of Asp555 and Asn540 in two conformations, and the 4-methylphenyl group is bound in a hydrophobic pocket in the catalytic center. Our elucidation of the binding mode of this compound can be expected to facilitate the rational design of more-potent reversible LSD1 inhibitors. Full article
(This article belongs to the Special Issue Modulators of Histone Methylation: A Medicinal Chemistry Perspective)
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12 pages, 1387 KiB  
Article
Prognostic Significance of Activated Leukocyte Cell Adhesion Molecule (ALCAM) in Association with Promoter Methylation of the ALCAM Gene in Breast Cancer
by Young Ju Jeong, Hoon Kyu Oh, Sung Hwan Park and Jin Gu Bong
Molecules 2018, 23(1), 131; https://doi.org/10.3390/molecules23010131 - 9 Jan 2018
Cited by 10 | Viewed by 4528
Abstract
Activated leukocyte cell adhesion molecule (ALCAM) has been implicated in tumorigenesis. In this study, we studied DNA methylation status of the ALCAM gene using pyrosequencing in breast cancer tissues. We analyzed the association between the methylation status of the ALCAM gene and its [...] Read more.
Activated leukocyte cell adhesion molecule (ALCAM) has been implicated in tumorigenesis. In this study, we studied DNA methylation status of the ALCAM gene using pyrosequencing in breast cancer tissues. We analyzed the association between the methylation status of the ALCAM gene and its expression. Also, the effects of inflammation on the ALCAM gene methylation and its expression were investigated. The ALCAM gene methylation was associated with the ALCAM transcripts in tumor tissues. The methylation status of the ALCAM gene was not significantly different between tumor and normal tissues. The level of ALCAM transcripts was associated with the expression of TNFα, NF-κB p50, IL-4, and intratumoral inflammation. The IHC expression of ALCAM was associated with histologic grade, HER2 overexpression and molecular subtype. The expression of TNFα, NF-κB p50, and IL-4 showed significant association with the clinicopathologic characteristics. In conclusion, the ALCAM gene methylation was related to the level of ALCAM transcripts. Also, the level of ALCAM transcripts was associated with the inflammatory markers in breast cancer. Our results suggest that the methylation of the ALCAM gene contributes to the decreased expression of ALCAM. Also, ALCAM is linked to the inflammatory response in breast cancer. Full article
(This article belongs to the Special Issue Modulators of Histone Methylation: A Medicinal Chemistry Perspective)
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