| Literature DB >> 22823910 |
C David Andersson1, Tobias Karlberg, Torun Ekblad, Anders E G Lindgren, Ann-Gerd Thorsell, Sara Spjut, Urszula Uciechowska, Moritz S Niemiec, Pernilla Wittung-Stafshede, Johan Weigelt, Mikael Elofsson, Herwig Schüler, Anna Linusson.
Abstract
The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyzes the transfer of ADP-ribose units onto substrate proteins by using nicotinamide adenine dinucleotide (NAD(+)) as a cosubstrate. They have a documented role in chromatin remodelling and DNA repair, and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. By using virtual screening, we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers of the most promising hit compound confirmed binding in the low micromolar range to ARTD8. Crystal structures showed anchoring of the hits in the nicotinamide pocket. These results form a starting point in the development of chemical tools for the study of the role and function of ARTD7 and ARTD8.Entities:
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Year: 2012 PMID： 22823910 DOI： 10.1021/jm300746d
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446