Terminal deoxynucletidyl transferase (TdT) is overex- pressed in some cancer types, where it might compete with pol μ during the mutagenic repair of double strand breaks (DSBs) through the non- homologous end joining (NHEJ) pathway. Here we report the discovery and characterization of pyrrolyl and indolyl diketo acids that speci fi cally target TdT and behave as nucleotide-competitive inhibitors. These com- pounds 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, ex- plaining why these compounds are competitive inhibitors of the deoxy- nucleotide 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

New Nucleotide-Competitive Non-Nucleoside Inhibitors of Terminal 2 Deoxynucleotidyl Transferase: Discovery, Characterization, and 3 Crystal Structure in Complex with the Target / Costi, Roberta; CUZZUCOLI CRUCITTI, Giuliana; Pescatori, Luca; Messore, Antonella; Scipione, Luigi; Tortorella, Silvano; Alessandra, Amoroso; Emmanuele, Crespan; Pietro, Campiglia; Bruno, Maresca; Amalia, Porta; Ilaria, Granata; Ettore, Novellino; Jérôme, Gouge; Marc, Delarue; Giovanni, Maga; DI SANTO, Roberto. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 56:(2013), pp. 7431-7441. [10.1021/jm4010187]

New Nucleotide-Competitive Non-Nucleoside Inhibitors of Terminal 2 Deoxynucleotidyl Transferase: Discovery, Characterization, and 3 Crystal Structure in Complex with the Target

COSTI, Roberta;CUZZUCOLI CRUCITTI, GIULIANA;PESCATORI, LUCA;MESSORE, ANTONELLA;SCIPIONE, Luigi;TORTORELLA, Silvano;DI SANTO, Roberto
2013

Abstract

Terminal deoxynucletidyl transferase (TdT) is overex- pressed in some cancer types, where it might compete with pol μ during the mutagenic repair of double strand breaks (DSBs) through the non- homologous end joining (NHEJ) pathway. Here we report the discovery and characterization of pyrrolyl and indolyl diketo acids that speci fi cally target TdT and behave as nucleotide-competitive inhibitors. These com- pounds 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, ex- plaining why these compounds are competitive inhibitors of the deoxy- nucleotide 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
2013
01 Pubblicazione su rivista::01a Articolo in rivista
New Nucleotide-Competitive Non-Nucleoside Inhibitors of Terminal 2 Deoxynucleotidyl Transferase: Discovery, Characterization, and 3 Crystal Structure in Complex with the Target / Costi, Roberta; CUZZUCOLI CRUCITTI, Giuliana; Pescatori, Luca; Messore, Antonella; Scipione, Luigi; Tortorella, Silvano; Alessandra, Amoroso; Emmanuele, Crespan; Pietro, Campiglia; Bruno, Maresca; Amalia, Porta; Ilaria, Granata; Ettore, Novellino; Jérôme, Gouge; Marc, Delarue; Giovanni, Maga; DI SANTO, Roberto. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 56:(2013), pp. 7431-7441. [10.1021/jm4010187]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/525948
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