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PARP inhibitor with selectivity toward ADP-ribosyltransferase ARTD3/PARP3

Lindgren, Anders E G ; Karlberg, Tobias LU ; Thorsell, Ann-Gerd ; Hesse, Mareike ; Spjut, Sara ; Ekblad, Torun ; Andersson, C David ; Pinto, Ana Filipa ; Weigelt, Johan and Hottiger, Michael O , et al. (2013) In ACS Chemical Biology 8(8). p.703-1698
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... (More)

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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publishing date
type
Contribution to journal
publication status
published
keywords
ADP Ribose Transferases/antagonists & inhibitors, Catalytic Domain, Cell Line, Crystallography, X-Ray, Drug Delivery Systems, Drug Stability, Enzyme Activation/drug effects, Enzyme Inhibitors/chemistry, GPI-Linked Proteins/antagonists & inhibitors, Humans, Inhibitory Concentration 50, Models, Molecular, Molecular Structure, Niacinamide/chemistry, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases/chemistry, Quinazolinones/chemistry
in
ACS Chemical Biology
volume
8
issue
8
pages
6 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:84882762748
  • pmid:23742272
ISSN
1554-8937
DOI
10.1021/cb4002014
language
English
LU publication?
no
id
cd15670d-bfe9-4919-861b-1a8755fc0a46
date added to LUP
2024-11-21 17:56:24
date last changed
2025-04-11 21:51:53
@article{cd15670d-bfe9-4919-861b-1a8755fc0a46,
  abstract     = {{<p>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.</p>}},
  author       = {{Lindgren, Anders E G and Karlberg, Tobias and Thorsell, Ann-Gerd and Hesse, Mareike and Spjut, Sara and Ekblad, Torun and Andersson, C David and Pinto, Ana Filipa and Weigelt, Johan and Hottiger, Michael O and Linusson, Anna and Elofsson, Mikael and Schüler, Herwig}},
  issn         = {{1554-8937}},
  keywords     = {{ADP Ribose Transferases/antagonists & inhibitors; Catalytic Domain; Cell Line; Crystallography, X-Ray; Drug Delivery Systems; Drug Stability; Enzyme Activation/drug effects; Enzyme Inhibitors/chemistry; GPI-Linked Proteins/antagonists & inhibitors; Humans; Inhibitory Concentration 50; Models, Molecular; Molecular Structure; Niacinamide/chemistry; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases/chemistry; Quinazolinones/chemistry}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{8}},
  pages        = {{703--1698}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Chemical Biology}},
  title        = {{PARP inhibitor with selectivity toward ADP-ribosyltransferase ARTD3/PARP3}},
  url          = {{http://dx.doi.org/10.1021/cb4002014}},
  doi          = {{10.1021/cb4002014}},
  volume       = {{8}},
  year         = {{2013}},
}