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

    Costi, R. and Crucitti, G.C. and Pescatori, L. and Messore, A. and Scipione, L. and Tortorella, S. and Amoroso, A. and Crespan, E. and Campiglia, P. and Maresca, B. and Porta, A. and Granata, I. and Novellino, E. and Gouge, Jerome and Delarue, M. and Maga, G. and Di Santo, R. (2013) New nucleotide-competitive non-nucleoside inhibitors of terminal deoxynucleotidyl transferase: discovery, characterization, and crystal structure in complex with the target. Journal of Medicinal Chemistry 56 (18), pp. 7431-41. ISSN 0022-2623.

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    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.

    Metadata

    Item Type: Article
    School: School of Science > Biological Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Jerome Gouge
    Date Deposited: 06 Mar 2020 06:44
    Last Modified: 06 Mar 2020 06:44
    URI: https://eprints.bbk.ac.uk/id/eprint/31011

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