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Journal articles
New nucleotide-competitive non-nucleoside inhibitors of terminal deoxynucleotidyl transferase: discovery, characterization, and crystal structure in complex with the target.
Roberta Costi
1, *
Giuliana Cuzzucoli Crucitti
1
Luca Pescatori
1
Antonella Messore
1
Luigi Scipione
1
Silvano Tortorella
1
Alessandra Amoroso
2
Emmanuele Crespan
2
Pietro Campiglia
3
Bruno Maresca
3
Amalia Porta
3
Ilaria Granata
3
Ettore Novellino
4
Jérôme Gouge
5
Marc Delarue
5
Giovanni Maga
6
Roberto Di Santo
1
Roberta Costi 1
Correspondent author
Giuliana Cuzzucoli Crucitti 1
Author
Luca Pescatori 1
Author
Antonella Messore 1
Author
Luigi Scipione 1
Author
Silvano Tortorella 1
Author
Alessandra Amoroso 2
Author
Emmanuele Crespan 2
Author
Roberto Di Santo 1
Author
1
Department of Medicinal Chemistry and Technologies (Piazzale Aldo Moro 5, I-00185, Rome - Italy)
- Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti (Université de Rome La Sapienza 5 Place Aldo Moro 00185 Rome - Italy)
- RIIP - Réseau International des Instituts Pasteur (25, rue du Dr Roux 75724 Paris Cedex 15 - France)
- Università degli Studi di Roma "La Sapienza" [Rome] (Piazzale Aldo Moro 5, 00185 Roma - Italy)
3
Department of Pharmaceutical and Biomedical Sciences (Italy)
- UNISA - Università degli Studi di Salerno (Via Giovanni Paolo II, 132 - 84084 Fisciano (SA) - Italy)
4
Department of Pharmacy Naples (University of Naples Federico II, via D. Montesano 49, I-80131 Naples - Italy)
- Université de Naples (France)
5
DSM - Dynamique Structurale des Macromolécules (25-28 rue du Docteur Roux F-75724 Paris Cedex 15 - France)
- Institut Pasteur [Paris] (25-28, rue du docteur Roux, 75724 Paris cedex 15 - France)
- CNRS - Centre National de la Recherche Scientifique : URA2185 (France)
6
DNA Enzymology and Molecular Virology Section (Institute of Molecular Genectics-CNR National Research Council via Abbiategrasso 207 I-27100 Pavia - Italy)
Abstract : Terminal deoxynucletidyl transferase (TdT) is overexpressed in some cancer types, where it might compete with pol μ during the mutagenic repair of double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. Here we report the discovery and characterization of pyrrolyl and indolyl diketo acids that specifically target TdT and behave as nucleotide-competitive inhibitors. These compounds show a selective toxicity toward MOLT-4 compared to HeLa cells that correlate well with in vitro selectivity for TdT. The binding site of two of these inhibitors was determined by cocrystallization with TdT, explaining why these compounds are competitive inhibitors of the deoxynucleotide triphosphate (dNTP). In addition, because of the observed dual localization of the phenyl substituent, these studies open the possibility of rationally designing more potent compounds.
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https://hal-riip.archives-ouvertes.fr/pasteur-00968827
Contributor : Istituto Pasteur Fondazione Cenci Bolognetti <>
Submitted on : Tuesday, April 1, 2014 - 4:01:57 PM
Last modification on : Wednesday, October 28, 2020 - 3:20:08 PM
Long-term archiving on: : Monday, April 10, 2017 - 8:17:24 AM
Contributor : Istituto Pasteur Fondazione Cenci Bolognetti <>
Submitted on : Tuesday, April 1, 2014 - 4:01:57 PM
Last modification on : Wednesday, October 28, 2020 - 3:20:08 PM
Long-term archiving on: : Monday, April 10, 2017 - 8:17:24 AM
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Identifiers
- HAL Id : pasteur-00968827, version 1
- DOI : 10.1021/jm4010187
- PUBMED : 23968551
Citation
Roberta Costi, Giuliana Cuzzucoli Crucitti, Luca Pescatori, Antonella Messore, Luigi Scipione, et al.. New nucleotide-competitive non-nucleoside inhibitors of terminal deoxynucleotidyl transferase: discovery, characterization, and crystal structure in complex with the target.. Journal of Medicinal Chemistry, American Chemical Society, 2013, 56 (18), pp.7431-41. ⟨10.1021/jm4010187⟩. ⟨pasteur-00968827⟩
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