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Eur J Med Chem. 2015 May 5;95:546-51. doi: 10.1016/j.ejmech.2015.03.067. Epub 2015 Apr 1.

Towards small molecule inhibitors of mono-ADP-ribosyltransferases.

Author information

1
Department of Medicinal Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
2
Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
3
Department of Medicinal Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden. Electronic address: herwig.schuler@ki.se.
4
Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden. Electronic address: mikael.elofsson@chem.umu.se.

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 ARTD1/PARP1. The most potent compound inhibits ARTD10 with sub-micromolar IC50.

KEYWORDS:

ARTD inhibitor; Diphtheria toxin-like ADP-ribosyltransferase; Mono-ADP-ribosyltransferase; PARP inhibitor; Poly(ADP-ribose) polymerase; mART

PMID:
25847771
DOI:
10.1016/j.ejmech.2015.03.067
[Indexed for MEDLINE]
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