PARP inhibitor with selectivity toward ADP-ribosyltransferase ARTD3/PARP3.

Lindgren AE, Karlberg T, Thorsell AG, Hesse M, Spjut S, Ekblad T, Andersson CD, Pinto AF, Weigelt J, Hottiger MO, Linusson A, Elofsson M, Schüler H

ACS Chem. Biol. 8 (8) 1698-1703 [2013-08-16; online 2013-06-08]

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.

Protein Science Facility (PSF)

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PubMed 23742272

DOI 10.1021/cb4002014

Crossref 10.1021/cb4002014

PDB 4GV0

PDB 4GV2

PDB 4GV4

PDB 4GV7