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Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach...
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Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 7981

Special Issue Editors

Prof. Dr. Olga Lavrik

E-Mail Website
Guest Editor
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Interests: molecular biology; structural biology; cancer research
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Konstantin Volcho

E-Mail Website
Guest Editor
Department of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentjev av. 9, 630090 Novosibirsk, Russia
Interests: medicinal chemistry; molecular biology; cancer research
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The cytotoxic effect of chemotherapy and radiotherapy of cancer is associated with their capacity to generate DNA damage. The ability of cancer cells to recognize DNA damage and initiate DNA repair is a key mechanism for therapeutic resistance to chemotherapy. Therefore, the targeting of DNA repair enzymes can be used as a strategy to potentiate the cytotoxicity of the currently available DNA damaging agents toward cancer cells. Inhibitors of PARP1 (poly(ADP-ribose)polymerase 1, the enzyme involved in DNA repair) such as olaparib, rucaparib, and niraparib are in clinical use already. Thus, the search and study of therapeutic targets among DNA repair enzymes and factors, as well as development of new inhibitors of DNA repair enzymes, is an important and topical task.  Medicinal chemists, bioorganic chemists, physical chemists, biologists, and pharmacologists contribute significantly to these multidisciplinary studies. A Special Issue of the International Journal of Molecular Sciences provides a great opportunity for a thorough discussion of the state of the art in this area.

Prof. Dr. Olga Lavrik
Prof. Dr. Konstantin Volcho
Guest Editors

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • DNA repair
  • enzymes
  • poly(ADP-ribose)polymerases
  • tyrosyl–DNA phosphodiesterases
  • DNA glycosylases
  • AP endonucleases
  • poly(ADP-ribose) glycohydrolase
  • DNA polymerase β
  • anticancer therapy
  • DNA repair inhibitors

Related Special Issue

Published Papers (3 papers)

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Research

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17 pages, 2744 KiB  
Article
Novel TDP1 Inhibitors: Disubstituted Thiazolidine-2,4-Diones Containing Monoterpene Moieties
by Dmitry I. Ivankin, Tatyana E. Kornienko, Marina A. Mikhailova, Nadezhda S. Dyrkheeva, Alexandra L. Zakharenko, Chigozie Achara, Jóhannes Reynisson, Victor M. Golyshev, Olga A. Luzina, Konstantin P. Volcho, Nariman F. Salakhutdinov and Olga I. Lavrik
Int. J. Mol. Sci. 2023, 24(4), 3834; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043834 - 14 Feb 2023
Cited by 4 | Viewed by 1556
Abstract
Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy; the use of TDP1 inhibitors with a topoisomerase 1 poison such as topotecan is a potential combination therapy. In this work, a novel series of 3,5-disubstituted thiazolidine-2,4-diones was synthesized and tested against TDP1. [...] Read more.
Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy; the use of TDP1 inhibitors with a topoisomerase 1 poison such as topotecan is a potential combination therapy. In this work, a novel series of 3,5-disubstituted thiazolidine-2,4-diones was synthesized and tested against TDP1. The screening revealed some active compounds with IC50 values less than 5 μM. Interestingly, compounds 20d and 21d were the most active, with IC50 values in the submicromolar concentration range. None of the compounds showed cytotoxicity against HCT-116 (colon carcinoma) and MRC-5 (human lung fibroblasts) cell lines in the 1–100 μM concentration range. Finally, this class of compounds did not sensitize cancer cells to the cytotoxic effect of topotecan. Full article
(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach 2.0)
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Review

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16 pages, 1238 KiB  
Review
Polθ Inhibition: An Anticancer Therapy for HR-Deficient Tumours
by Gabriela Barszczewska-Pietraszek, Małgorzata Drzewiecka, Piotr Czarny, Tomasz Skorski and Tomasz Śliwiński
Int. J. Mol. Sci. 2023, 24(1), 319; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010319 - 24 Dec 2022
Cited by 2 | Viewed by 2919
Abstract
DNA polymerase theta (Polθ)-mediated end joining (TMEJ) is, along with homologous recombination (HR) and non-homologous end-joining (NHEJ), one of the most important mechanisms repairing potentially lethal DNA double-strand breaks (DSBs). Polθ is becoming a new target in cancer research because it demonstrates numerous [...] Read more.
DNA polymerase theta (Polθ)-mediated end joining (TMEJ) is, along with homologous recombination (HR) and non-homologous end-joining (NHEJ), one of the most important mechanisms repairing potentially lethal DNA double-strand breaks (DSBs). Polθ is becoming a new target in cancer research because it demonstrates numerous synthetically lethal interactions with other DNA repair mechanisms, e.g., those involving PARP1, BRCA1/2, DNA-PK, ATR. Inhibition of Polθ could be achieved with different methods, such as RNA interference (RNAi), CRISPR/Cas9 technology, or using small molecule inhibitors. In the context of this topic, RNAi and CRISPR/Cas9 are still more often applied in the research itself rather than clinical usage, different than small molecule inhibitors. Several Polθ inhibitors have been already generated, and two of them, novobiocin (NVB) and ART812 derivative, are being tested in clinical trials against HR-deficient tumors. In this review, we describe the significance of Polθ and the Polθ-mediated TMEJ pathway. In addition, we summarize the current state of knowledge about Polθ inhibitors and emphasize the promising role of Polθ as a therapeutic target. Full article
(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach 2.0)
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19 pages, 1843 KiB  
Review
DNA Demethylation in the Processes of Repair and Epigenetic Regulation Performed by 2-Ketoglutarate-Dependent DNA Dioxygenases
by Nikita A. Kuznetsov, Lyubov Yu. Kanazhevskaya and Olga S. Fedorova
Int. J. Mol. Sci. 2021, 22(19), 10540; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910540 - 29 Sep 2021
Cited by 6 | Viewed by 2670
Abstract
Site-specific DNA methylation plays an important role in epigenetic regulation of gene expression. Chemical methylation of DNA, including the formation of various methylated nitrogenous bases, leads to the formation of genotoxic modifications that impair DNA functions. Despite the fact that different pathways give [...] Read more.
Site-specific DNA methylation plays an important role in epigenetic regulation of gene expression. Chemical methylation of DNA, including the formation of various methylated nitrogenous bases, leads to the formation of genotoxic modifications that impair DNA functions. Despite the fact that different pathways give rise to methyl groups in DNA, the main pathway for their removal is oxidative demethylation, which is catalyzed by nonheme Fe(II)/α-ketoglutarate–dependent DNA dioxygenases. DNA dioxygenases share a common catalytic mechanism of the oxidation of the alkyl groups on nitrogenous bases in nucleic acids. This review presents generalized data on the catalytic mechanism of action of DNA dioxygenases and on the participation of typical representatives of this superfamily, such as prokaryotic enzyme AlkB and eukaryotic enzymes ALKBH1–8 and TET1–3, in both processes of direct repair of alkylated DNA adducts and in the removal of an epigenetic mark (5-methylcytosine). Full article
(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach 2.0)
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