PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP3
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- 作者：Anders E. G. Lindgren ; Tobias Karlberg ; Ann-Gerd Thorsell ; Mareike Hesse ; Sara Spjut ; Torun Ekblad ; C. David Andersson ; Ana Filipa Pinto ; Johan Weigelt ; Michael O. Hottiger ; Anna Linusson ; Mikael Elofsson ; Herwig Sch眉ler
- 刊名：ACS Chemical Biology
- 出版年：2013
- 出版时间：August 16, 2013
- 年：2013
- 卷：8
- 期：8
- 页码：1698-1703
- 全文大小：415K
- 年卷期：v.8,no.8(August 16, 2013)
- ISSN：1554-8937
文摘
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.