title: 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.
authors: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma , P.le Aldo Moro 5, I-00185 Roma, Italy.
authors: Roberta
authors: R
authors: Costi
authors: Giuliana Cuzzucoli
authors: GC
authors: Crucitti
authors: Luca
authors: L
authors: Pescatori
authors: Antonella
authors: A
authors: Messore
authors: Luigi
authors: L
authors: Scipione
authors: Silvano
authors: S
authors: Tortorella
authors: Alessandra
authors: A
authors: Amoroso
authors: Emmanuele
authors: E
authors: Crespan
authors: Pietro
authors: P
authors: Campiglia
authors: Bruno
authors: B
authors: Maresca
authors: Amalia
authors: A
authors: Porta
authors: Ilaria
authors: I
authors: Granata
authors: Ettore
authors: E
authors: Novellino
authors: Jérôme
authors: J
authors: Gouge
authors: Marc
authors: M
authors: Delarue
authors: Giovanni
authors: G
authors: Maga
authors: Roberto
authors: R
authors: Di Santo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001667:Binding, Competitive; D020134:Catalytic Domain; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004253:DNA Nucleotidylexotransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000378:metabolism; D003838:Deoxyadenine Nucleotides / Q000378:metabolism; D054306:Dideoxynucleotides / Q000378:metabolism; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006603:Hexuronic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D009711:Nucleotides / Q000378:metabolism*
chemical_list: D004277:DNA, Single-Stranded; D003838:Deoxyadenine Nucleotides; D054306:Dideoxynucleotides; D004791:Enzyme Inhibitors; D006603:Hexuronic Acids; D009711:Nucleotides; C095263:hexenuronic acid; C037773:2',3'-dideoxyadenosine triphosphate; D004253:DNA Nucleotidylexotransferase