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Towards small molecule inhibitors of mono-ADP-ribosyltransferases

Ekblad, Torun ; Lindgren, Anders E G ; Andersson, C David ; Caraballo, Rémi ; Thorsell, Ann-Gerd ; Karlberg, Tobias LU ; Spjut, Sara ; Linusson, Anna ; Schüler, Herwig LU orcid and Elofsson, Mikael (2015) In European Journal of Medicinal Chemistry 95. p.51-546
Abstract

Protein ADP-ribosylation is a post-translational modification involved in DNA repair, protein degradation, transcription regulation, and epigenetic events. Intracellular ADP-ribosylation is catalyzed predominantly by ADP-ribosyltransferases with diphtheria toxin homology (ARTDs). The most prominent member of the ARTD family, poly(ADP-ribose) polymerase-1 (ARTD1/PARP1) has been a target for cancer drug development for decades. Current PARP inhibitors are generally non-selective, and inhibit the mono-ADP-ribosyltransferases with low potency. Here we describe the synthesis of acylated amino benzamides and screening against the mono-ADP-ribosyltransferases ARTD7/PARP15, ARTD8/PARP14, ARTD10/PARP10, and the poly-ADP-ribosyltransferase... (More)

Protein ADP-ribosylation is a post-translational modification involved in DNA repair, protein degradation, transcription regulation, and epigenetic events. Intracellular ADP-ribosylation is catalyzed predominantly by ADP-ribosyltransferases with diphtheria toxin homology (ARTDs). The most prominent member of the ARTD family, poly(ADP-ribose) polymerase-1 (ARTD1/PARP1) has been a target for cancer drug development for decades. Current PARP inhibitors are generally non-selective, and inhibit the mono-ADP-ribosyltransferases with low potency. Here we describe the synthesis of acylated amino benzamides and screening against the mono-ADP-ribosyltransferases ARTD7/PARP15, ARTD8/PARP14, ARTD10/PARP10, and the poly-ADP-ribosyltransferase ARTD1/PARP1. The most potent compound inhibits ARTD10 with sub-micromolar IC50.

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author
; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
ADP Ribose Transferases/antagonists & inhibitors, Drug Evaluation, Preclinical, Enzyme Inhibitors/pharmacology, Humans, Inhibitory Concentration 50, Small Molecule Libraries/pharmacology
in
European Journal of Medicinal Chemistry
volume
95
pages
6 pages
publisher
Elsevier Masson SAS
external identifiers
  • pmid:25847771
  • scopus:84926206190
ISSN
0223-5234
DOI
10.1016/j.ejmech.2015.03.067
language
English
LU publication?
no
additional info
Copyright © 2015 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
id
864d52f5-9c8d-4782-9155-37ee0b2cd542
date added to LUP
2024-11-21 17:54:02
date last changed
2025-06-20 21:11:44
@article{864d52f5-9c8d-4782-9155-37ee0b2cd542,
  abstract     = {{<p>Protein ADP-ribosylation is a post-translational modification involved in DNA repair, protein degradation, transcription regulation, and epigenetic events. Intracellular ADP-ribosylation is catalyzed predominantly by ADP-ribosyltransferases with diphtheria toxin homology (ARTDs). The most prominent member of the ARTD family, poly(ADP-ribose) polymerase-1 (ARTD1/PARP1) has been a target for cancer drug development for decades. Current PARP inhibitors are generally non-selective, and inhibit the mono-ADP-ribosyltransferases with low potency. Here we describe the synthesis of acylated amino benzamides and screening against the mono-ADP-ribosyltransferases ARTD7/PARP15, ARTD8/PARP14, ARTD10/PARP10, and the poly-ADP-ribosyltransferase ARTD1/PARP1. The most potent compound inhibits ARTD10 with sub-micromolar IC50.</p>}},
  author       = {{Ekblad, Torun and Lindgren, Anders E G and Andersson, C David and Caraballo, Rémi and Thorsell, Ann-Gerd and Karlberg, Tobias and Spjut, Sara and Linusson, Anna and Schüler, Herwig and Elofsson, Mikael}},
  issn         = {{0223-5234}},
  keywords     = {{ADP Ribose Transferases/antagonists & inhibitors; Drug Evaluation, Preclinical; Enzyme Inhibitors/pharmacology; Humans; Inhibitory Concentration 50; Small Molecule Libraries/pharmacology}},
  language     = {{eng}},
  month        = {{05}},
  pages        = {{51--546}},
  publisher    = {{Elsevier Masson SAS}},
  series       = {{European Journal of Medicinal Chemistry}},
  title        = {{Towards small molecule inhibitors of mono-ADP-ribosyltransferases}},
  url          = {{http://dx.doi.org/10.1016/j.ejmech.2015.03.067}},
  doi          = {{10.1016/j.ejmech.2015.03.067}},
  volume       = {{95}},
  year         = {{2015}},
}