Skip to Main content Skip to Navigation
Journal articles

New nucleotide-competitive non-nucleoside inhibitors of terminal deoxynucleotidyl transferase: discovery, characterization, and crystal structure in complex with the target.

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.
Document type :
Journal articles
Complete list of metadatas

Cited literature [14 references]  Display  Hide  Download

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

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

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⟩

Share

Metrics

Record views

225