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.
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We thank Dr. M. Einarson of the FCCC Translational Facility for her advice and assistance with small-molecule collection screening experiments, Dr. I. Serebriiskii for helpful discussions, and Dr. M. Robinson for BT474 and HR6 breast cancer cell lines. The research was supported by grants from the National Institutes of Health (R01 DK082623) to A.V.T.
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