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

DOI: 10.1021/cb4002014 DOI Help
PMID: 23742272 PMID Help

Authors: Anders E. G. Lindgren (Umeå University) , Tobias Karlberg (Karolinska Institutet) , Ann-gerd Thorsell (Karolinska Institutet) , Mareike Hesse (University of Zurich) , Sara Spjut (Umeå University) , Torun Ekblad (Karolinska Institutet) , C. David Andersson (Umeå University) , Ana Filipa Pinto (Karolinska Institutet) , Johan Weigelt (Karolinska Institutet) , Michael O. Hottiger (University of Zurich) , Anna Linusson (Umeå University) , Mikael Elofsson (Umeå University) , Herwig Schüler (Karolinska Institutet)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology , VOL 8 (8)

State: Published (Approved)
Published: June 2013
Diamond Proposal Number(s): 6603

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 relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.

Journal Keywords: Catalytic; Cell; Crystallography; X-Ray; Drug; Drug; Enzyme; Enzyme; GPI-Linked; Humans; Inhibitory; Models; Molecular; Niacinamide; Poly(ADP-ribose); Quinazolinones

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Other Facilities: ID14.4 at ESRF (Grenoble, France)BL14.1 at BESSY (Berlin, Germany)

Added On: 12/06/2013 14:10

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