title: Small-molecule collection and high-throughput colorimetric assay to identify PARP1 inhibitors.
abstract: During the last few years, poly(ADP-ribose)polymerase (PARP) proteins became a very popular target for anticancer treatment. Many PARP inhibitors have been generated and tested by pharmacological industry. However, most of them were designed to disrupt the DNA-dependent PARP1 protein activation pathway and were based on a competition with NAD for a binding site on PARP molecule and, therefore, on disruption of PARP-mediated enzymatic reaction. This limitation resulted in a discovery of mainly nucleotide-like PARP1 inhibitors which may target not only PARP, but also other pathways involving NAD and other nucleotides. Here, we describe a strategy for the identification of PARP inhibitors that target a different pathway, the histone H4-dependent PARP1 activation. Besides the identification of NAD competitors in a small-molecule collection, this approach allows finding novel classes of PARP inhibitors that specifically disrupt H4-based PARP activation.
authors.affiliation: Epigenetics and Progenitor Cells Program, Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Kotova
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Pinnola
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Tulin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D003124:Colorimetry / Q000379:methods*; D004330:Drosophila; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors