Small-molecule collection and high-throughput colorimetric assay to identify PARP1 inhibitors.

Kotova E, Pinnola AD, Tulin AV.

Methods Mol Biol. 2011; 780: 491–516.

During the last few years, Poly(ADP-ribose)Polymerase (PARP) proteins became a very popular target for anti-cancer 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 PARP inhibitors that target a different pathway, the histone H4 dependent PARP1 activation. Besides the identification of NAD competitors in a small molecules collection, this approach allows finding novel classes of PARP inhibitors that specifically disrupt H4 based PARP activation.
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