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https://www.readbyqxmd.com/read/29677635/synthesis-and-structure-activity-relationship-of-furoquinolinediones-as-inhibitors-of-tyrosyl-dna-phosphodiesterase-2-tdp2
#1
Le-Mao Yu, Zhu Hu, Yu Chen, Azhar Ravji, Sophia Lopez, Caroline B Plescia, Qian Yu, Hui Yang, Monica Abdelmalak, Sourav Saha, Keli Agama, Evgeny Kiselev, Christophe Marchand, Yves Pommier, Lin-Kun An
Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a recently discovered enzyme specifically repairing topoisomerase II (TOP2)-mediated DNA damage. It has been shown that inhibition of TDP2 synergize with TOP2 inhibitors. Herein, we report the discovery of the furoquinolinedione chemotype as a suitable skeleton for the development of selective TDP2 inhibitors. Compound 1 was identified as a TDP2 inhibitor as a result of screening our in-house compound library for compounds selective for TDP2 vs. TDP1. Further SAR studies provide several selective TDP2 inhibitors at low-micromolar range...
April 12, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29597329/the-human-tyrosyl-dna-phosphodiesterase-1-htdp1-inhibitor-nsc120686-as-an-exploratory-tool-to-investigate-plant-tdp1-genes
#2
Anca Macovei, Andrea Pagano, Maria Elisa Sabatini, Sofia Grandi, Alma Balestrazzi
The hTdp1 (human tyrosyl-DNA phosphodiesterase 1) inhibitor NSC120686 has been used, along with topoisomerase inhibitors, as a pharmacophoric model to restrain the Tdp1 activity as part of a synergistic treatment for cancer. While this compound has an end-point application in medical research, in plants, its application has not been considered so far. The originality of our study consists in the use of hTdp1 inhibitor in Medicago truncatula cells, which, unlike human cells, contain two Tdp1 genes. Hence, the purpose of this study was to test the hTdp1 inhibitor NSC120686 as an exploratory tool to investigate the plant Tdp1 genes, since their characterization is still in incipient phases...
March 28, 2018: Genes
https://www.readbyqxmd.com/read/29562592/novel-semisynthetic-derivatives-of-bile-acids-as-effective-tyrosyl-dna-phosphodiesterase-1-inhibitors
#3
Oksana V Salomatina, Irina I Popadyuk, Alexandra L Zakharenko, Olga D Zakharova, Dmitriy S Fadeev, Nina I Komarova, Jóhannes Reynisson, H John Arabshahi, Raina Chand, Konstantin P Volcho, Nariman F Salakhutdinov, Olga I Lavrik
An Important task in the treatment of oncological and neurodegenerative diseases is the search for new inhibitors of DNA repair system enzymes. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the DNA repair system enzymes involved in the removal of DNA damages caused by topoisomerase I inhibitors. Thus, reducing the activity of Tdp1 can increase the effectiveness of currently used anticancer drugs. We describe here a new class of semisynthetic small molecule Tdp1 inhibitors based on the bile acid scaffold that were originally identified by virtual screening...
March 17, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29523818/reactive-oxygen-species-stress-increases-accumulation-of-tyrosyl-dna-phsosphodiesterase-1-within-mitochondria
#4
Hok Khim Fam, Kunho Choi, Lauren Fougner, Chinten James Lim, Cornelius F Boerkoel
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a nuclear and mitochondrial protein that in nuclei and in vitro repairs blocked 3' DNA termini such as 3' phosphotyrosine conjugates resulting from stalling of topoisomerase I-DNA intermediates. Its mutation also causes spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1). Because Tdp1 colocalizes with mitochondria following oxidative stress, we hypothesized that Tdp1 repairs mitochondrial DNA (mtDNA) and that mtDNA damage mediates entry of Tdp1 into the mitochondria...
March 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29295983/structural-basis-for-dna-3-end-processing-by-human-tyrosyl-dna-phosphodiesterase-1
#5
Fiona J Flett, Emilija Ruksenaite, Lee A Armstrong, Shipra Bharati, Roberta Carloni, Elizabeth R Morris, C Logan Mackay, Heidrun Interthal, Julia M Richardson
Tyrosyl-DNA phosphodiesterase (Tdp1) is a DNA 3'-end processing enzyme that repairs topoisomerase 1B-induced DNA damage. We use a new tool combining site-specific DNA-protein cross-linking with mass spectrometry to identify Tdp1 interactions with DNA. A conserved phenylalanine (F259) of Tdp1, required for efficient DNA processing in biochemical assays, cross-links to defined positions in DNA substrates. Crystal structures of Tdp1-DNA complexes capture the DNA repair machinery after 3'-end cleavage; these reveal how Tdp1 coordinates the 3'-phosphorylated product of nucleosidase activity and accommodates duplex DNA...
January 2, 2018: Nature Communications
https://www.readbyqxmd.com/read/29248742/aminoadamantanes-containing-monoterpene-derived-fragments-as-potent-tyrosyl-dna-phosphodiesterase-1-inhibitors
#6
Konstantin Yu Ponomarev, Evgeniy V Suslov, Alexandra L Zakharenko, Olga D Zakharova, Artem D Rogachev, Dina V Korchagina, Ayesha Zafar, Jóhannes Reynisson, Andrey A Nefedov, Konstantin P Volcho, Nariman F Salakhutdinov, Olga I Lavrik
The ability of a number of nitrogen-containing compounds that simultaneously carry the adamantane and monoterpene moieties to inhibit Tdp1, an important enzyme of the DNA repair system, is studied. Inhibition of this enzyme has the potential to overcome chemotherapeutic resistance of some tumor types. Compound (+)-3c synthesized from 1-aminoadamantane and (+)-myrtenal, and compound 4a produced from 2-aminoadamantane and citronellal were found to be most potent as they inhibited Tdp1 with IC50 values of 6 and 3...
February 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29216365/tyrosyl-dna-phosphodiesterases-rescuing-the-genome-from-the-risks-of-relaxation
#7
Ajinkya S Kawale, Lawrence F Povirk
Tyrosyl-DNA Phosphodiesterases 1 (TDP1) and 2 (TDP2) are eukaryotic enzymes that clean-up after aberrant topoisomerase activity. While TDP1 hydrolyzes phosphotyrosyl peptides emanating from trapped topoisomerase I (Top I) from the 3' DNA ends, topoisomerase 2 (Top II)-induced 5'-phosphotyrosyl residues are processed by TDP2. Even though the canonical functions of TDP1 and TDP2 are complementary, they exhibit little structural or sequence similarity. Homozygous mutations in genes encoding these enzymes lead to the development of severe neurodegenerative conditions due to the accumulation of transcription-dependent topoisomerase cleavage complexes underscoring the biological significance of these enzymes in the repair of topoisomerase-DNA lesions in the nervous system...
January 25, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29177742/studying-tdp1-function-in-dna-repair
#8
Shih-Chieh Chiang, Kirsty Liversidge, Sherif F El-Khamisy
Topoisomerase poisons act by inducing abortive topoisomerase reactions, which generate stable protein-DNA breaks (PDBs) that interfere with transcription elongation and progression of replication forks. In vertebrates, Tyrosyl-DNA phosphodiesterase 1 (TDP1) plays a major role in removal of topoisomerase 1-associated PDBs in the nucleus and mitochondria by hydrolyzing the 3'-phosphotyrosine bond. Depletion of TDP1 sensitizes tumor cells with defective DNA repair capacity to the genotoxic effect of TOP1 poisons, while homozygous mutation of the catalytic residue of TDP1 is associated with cerebellar degeneration and ataxia...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29167313/mechanism-informed-repurposing-of-minocycline-overcomes-resistance-to-topoisomerase-inhibition-for-peritoneal-carcinomatosis
#9
Huang-Chiao Huang, Joyce Liu, Yan Baglo, Imran Rizvi, Sriram Anbil, Michael Pigula, Tayyaba Hasan
Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and rapid route toward addressing the burgeoning problem of plateauing of effective therapeutics for drug-resistant micrometastases. We show that the antibiotic minocycline, by its ability to minimize DNA repair via reduced expression of tyrosyl-DNA phosphodiesterase-1 (Tdp1), removes a key process attenuating the efficacy of irinotecan, a frequently used chemotherapeutic against metastatic disease. Moreover, minocycline and irinotecan cooperatively mitigate each other's undesired cytokine inductions of VEGF and IL8, respectively, thereby reinforcing the benefits of each modality...
February 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29100039/xrcc1-mediated-repair-of-strand-breaks-independent-of-pnkp-binding
#10
Julie K Horton, Donna F Stefanick, Ming-Lang Zhao, Agnes K Janoshazi, Natalie R Gassman, Hannah J Seddon, Samuel H Wilson
Repair of DNA-protein crosslinks and oxidatively damaged DNA base lesions generates intermediates with nicks or gaps with abnormal and blocked 3'-phosphate and 5'-OH ends that prevent the activity of DNA polymerases and ligases. End cleaning in mammalian cells by Tdp1 and PNKP produces the conventional 3'-OH and 5'-phosphate DNA ends suitable for completion of repair. This repair function of PNKP is facilitated by its binding to the scaffold protein XRCC1, and phosphorylation of XRCC1 by CK2 at several consensus sites enables PNKP binding and recruitment to DNA damage...
December 2017: DNA Repair
https://www.readbyqxmd.com/read/29099800/the-tyrosyl-dna-phosphodiesterase-1%C3%AE-tdp1%C3%AE-gene-discloses-an-early-response-to-abiotic-stresses
#11
Maria Elisa Sabatini, Andrea Pagano, Susana Araùjo, Alma Balestrazzi, Anca Macovei
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is involved in DNA repair pathways as it mends the topoisomerase I-DNA covalent complexes. In plants, a small Tdp1 gene family, composed by Tdp1α and Tdp1β genes, was identified, but the roles of these genes in abiotic stress responses are not fully understood. To investigate their specific stress response patterns, the present study made use of bioinformatic and molecular tools to look into the Tdp1β gene function, so far described only in the plant kingdom, and compare it with Tdp1α gene coding for the canonical, highly conserved α isoform...
November 3, 2017: Genes
https://www.readbyqxmd.com/read/29078113/tdp1-is-required-for-efficient-non-homologous-end-joining-in-human-cells
#12
Jing Li, Matthew Summerlin, Karin C Nitiss, John L Nitiss, Leslyn A Hanakahi
Tyrosyl-DNA phosphodiesterase 1 (TDP1) can remove a wide variety of 3' and 5' terminal DNA adducts. Genetic studies in yeast identified TDP1 as a regulator of non-homologous end joining (NHEJ) fidelity in the repair of double-strand breaks (DSBs) lacking terminal adducts. In this communication, we show that TDP1 plays an important role in joining cohesive DSBs in human cells. To investigate the role of TDP1 in NHEJ in live human cells we used CRISPR/cas9 to produce TDP1-knockout (TDP1-KO) HEK-293 cells. As expected, human TDP1-KO cells were highly sensitive to topoisomerase poisons and ionizing radiation...
December 2017: DNA Repair
https://www.readbyqxmd.com/read/29037996/synthesis-anti-cancer-screening-and-tyrosyl-dna-phosphodiesterase-1-tdp1-inhibition-activity-of-novel-piperidinyl-sulfamides
#13
Jung Ho Jun, Vineet Kumar, Thomas S Dexheimer, Iwona Wedlich, Marc C Nicklaus, Yves Pommier, Sanjay V Malhotra
Novel piperidinyl-based sulfamide derivatives were designed and synthesized through various synthetic routes. Anticancer activities of these sulfamides were evaluated by phenotypic screening on National Cancer Institute's 60 human tumor cell lines (NCI-60). Preliminary screening at 10μM concentration showed that piperidinyl sulfamide aminoester 26 (NSC 749204) was sensitive to most of the cell lines in the panel. Further dose-response studies showed that 26 was highly selective for inhibition of colon cancer cell lines with minimum GI50=1...
October 13, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28993637/htlv-1-bzip-factor-suppresses-tdp1-expression-through-inhibition-of-nrf-1-in-adult-t-cell-leukemia
#14
Yoko Takiuchi, Masayuki Kobayashi, Kohei Tada, Fumie Iwai, Maki Sakurada, Shigeki Hirabayashi, Kayoko Nagata, Kotaro Shirakawa, Keisuke Shindo, Jun-Ichirou Yasunaga, Yasuhiro Murakawa, Vinodh Rajapakse, Yves Pommier, Masao Matsuoka, Akifumi Takaori-Kondo
Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). We recently reported that abacavir, an anti-HIV-1 drug, potently and selectively kills ATL cells. This effect was attributed to the reduced expression of tyrosyl-DNA-phosphodiesterase 1 (TDP1), a DNA repair enzyme, in ATL cells. However, the molecular mechanism underlying the downregulation of TDP1 in ATL cells remains elusive. Here we identified the core promoter of the TDP1 gene, which contains a conserved nuclear respiratory factor 1 (NRF-1) binding site...
October 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28974547/common-tdp1-polymorphisms-in-relation-to-survival-among-small-cell-lung-cancer-patients-a-multicenter-study-from-the-international-lung-cancer-consortium
#15
Pawadee Lohavanichbutr, Lori C Sakoda, Christopher I Amos, Susanne M Arnold, David C Christiani, Michael P A Davies, John K Field, Eric B Haura, Rayjean J Hung, Takashi Kohno, Maria Teresa Landi, Geoffrey Liu, Yi Liu, Michael W Marcus, Grainne M O'Kane, Matthew B Schabath, Kouya Shiraishi, Stacey A Slone, Adonina Tardón, Ping Yang, Kazushi Yoshida, Ruyang Zhang, Xuchen Zong, Gary E Goodman, Noel S Weiss, Chu Chen
Purpose: DNA topoisomerase inhibitors are commonly used for treating small-cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single-nucleotide polymorphisms (SNP) are associated with overall survival among SCLC patients. Experimental Design: Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO)...
December 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28802254/tdp1-is-critical-for-the-repair-of-dna-breaks-induced-by-sapacitabine-a-nucleoside-also-targeting-atm-and-brca-deficient-tumors
#16
Muthana Al Abo, Hiroyuki Sasanuma, Xiaojun Liu, Vinodh N Rajapakse, Shar-Yin Huang, Evgeny Kiselev, Shunichi Takeda, William Plunkett, Yves Pommier
2'- C -cyano-2'-deoxy-1-β-d-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes β-elimination that generates single-strand breaks with abnormal 3'-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes nonphosphorylated 3'-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1- / - DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC...
November 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28740727/structure-modeling-of-human-tyrosyl-dna-phosphodiesterase-1-and-screening-for-its-inhibitors
#17
I V Gushchina, D K Nilov, A L Zakharenko, O I Lavrik, V K Švedas
The DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (Tdp1) represents a potential molecular target for anticancer therapy. A human Tdp1 model has been constructed using the methods of quantum and molecular mechanics, taking into account the ionization states of the amino acid residues in the active site and their interactions with the substrate and competitive inhibitors. The oligonucleotide- and phosphotyrosine-binding cavities important for the inhibitor design have been identified in the enzyme's active site...
April 2017: Acta Naturae
https://www.readbyqxmd.com/read/28697309/identification-of-natural-products-that-inhibit-the-catalytic-function-of-human-tyrosyl-dna-phosphodiesterase-tdp1
#18
Alun Bermingham, Edmund Price, Christophe Marchand, Adel Chergui, Alena Naumova, Emily L Whitson, Lauren R H Krumpe, Ekaterina I Goncharova, Jason R Evans, Tawnya C McKee, Curtis J Henrich, Yves Pommier, Barry R O'Keefe
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme crucial for cleavage of the covalent topoisomerase 1-DNA complex, an intermediate in DNA repair. TDP1 plays a role in reversing inhibition of topoisomerase I by camptothecins, a series of potent and effective inhibitors used in the treatment of colorectal, ovarian, and small-cell lung cancers. It is hypothesized that inhibition of TDP1 activity may enhance camptothecin sensitivity in tumors. Here, we describe the design, development, and execution of a novel assay to identify inhibitors of TDP1 present in natural product extracts...
July 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28657311/design-and-synthesis-of-chlorinated-and-fluorinated-7-azaindenoisoquinolines-as-potent-cytotoxic-anticancer-agents-that-inhibit-topoisomerase-i
#19
Mohamed S A Elsayed, Yafan Su, Ping Wang, Taresh Sethi, Keli Agama, Azhar Ravji, Christophe E Redon, Evgeny Kiselev, Katharine A Horzmann, Jennifer L Freeman, Yves Pommier, Mark Cushman
The 7-azaindenoisoquinolines are cytotoxic topoisomerase I (Top1) inhibitors. Previously reported representatives bear a 3-nitro group. The present report documents the replacement of the potentially genotoxic 3-nitro group by 3-chloro and 3-fluoro substituents, resulting in compounds with high Top1 inhibitory activities and potent cytotoxicities in human cancer cell cultures and reduced lethality in an animal model. Some of the new Top1 inhibitors also possess moderate inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2), two enzymes that are involved in DNA damage repair resulting from Top1 inhibitors, and they produce significantly more DNA damage in cancer cells than in normal cells...
July 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28550017/a-lysine-desert-protects-a-novel-domain-in-the-slx5-slx8-sumo-targeted-ub-ligase-to-maintain-sumoylation-levels-in-saccharomyces-cerevisiae
#20
Pragati Sharma, Janet R Mullen, Minxing Li, Mikel Zaratiegui, Samuel F Bunting, Steven J Brill
Protein modification by the small ubiquitin-like modifier (SUMO) plays important roles in genome maintenance. In Saccharomyces cerevisiae , proper regulation of sumoylation is known to be essential for viability in certain DNA repair mutants. Here, we find the opposite result; proper regulation of sumoylation is lethal in certain DNA repair mutants. Yeast cells lacking the repair factors TDP1 and WSS1 are synthetically lethal due to their redundant roles in removing Top1-DNA covalent complexes (Top1ccs). A screen for suppressors of tdp1 ∆ wss1 ∆ synthetic lethality isolated mutations in genes known to control global sumoylation levels including ULP1 , ULP2 , SIZ2 , and SLX5 The results suggest that alternative pathways of repair become available when sumoylation levels are altered...
August 2017: Genetics
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