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PARP inhibitor with selectivity toward ADP-ribosyltransferase ARTD3/PARP3


Lindgren, Anders E G; Karlberg, Tobias; Thorsell, Ann-Gerd; Hesse, Mareike; Spjut, Sara; Ekblad, Torun; Andersson, C David; Pinto, Ana Filipa; Weigelt, Johan; Hottiger, Michael O; Linusson, Anna; Elofsson, Mikael; Schüler, Herwig (2013). PARP inhibitor with selectivity toward ADP-ribosyltransferase ARTD3/PARP3. ACS Chemical Biology, 8(8):1698-1703.

Abstract

Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12 members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.

Abstract

Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12 members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Department of Molecular Mechanisms of Disease
07 Faculty of Science > Department of Molecular Mechanisms of Disease
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2013
Deposited On:30 Jan 2014 15:24
Last Modified:05 Apr 2016 17:25
Publisher:American Chemical Society
ISSN:1554-8929
Publisher DOI:https://doi.org/10.1021/cb4002014
PubMed ID:23742272

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