The poly ADP-ribose (ADPr) polymerase, PARP-1, is an essential protein involved in a wide range of cellular functions. On the molecular level, two pathways of PARP-1 activation have been identified: (1) DNA-dependent PARP-1 activation and (2) histone H4-dependent PARP-1 activation. PARP-1 inhibitors have been shown to selectively eliminate several types of tumorigenic cells. In recent years, PARP-1 inhibitors became popular in clinical research on novel strategies of cancer treatment and, a number of PARP-1 inhibitors are currently undergoing clinical trials for treatment of genetically disposed mutant tumors. Unfortunately, one of the factors that may limit the potency of PARP-1 inhibitors is the majority of currently available inhibitors were designed as nicotinamide adenine dinucleotide (NAD) competitors. NAD is abundant, ubiquitous, and is used by many other enzymes. Therefore, it is very difficult to completely eliminate NAD interaction with PARP-1 without drastically affecting other metabolic processes. Since PARP-1 remains a viable target in cancer therapy, there remains a need for PARP-1 inhibitors that do not affect other enzymes or other normal metabolic processes. Relatedly, there remains a need for PARP-1 inhibitors that diverge from the established model of aiming at the NAD-PARP-1 interaction.
Summary of the Invention
Researchers from Fox Chase Cancer Center observed that PARP-1 can be activated by interacting with core histone H4, that the catalytic domain of PARP-1 is responsible for its H4-dependent activation, and that this activation is stronger and more stable than the DNA-dependent activation of PARP-1. This observation led to development of an assay for identifying compounds that inhibit PARP-1 with specificity and potency, which are independent of nicotinamide adenine dinucleotide (NAD+). In addition to all known PARP-1 inhibitors, the pilot screening of test library identified seven molecules previously unknown as PARP-1 inhibitors. The developed assay is suitable for high-throughput screening of test compounds for the capacity to inhibit H4-dependent PARP-1 activation and is carried out in the absence of DNA.
Patent Status: Issued patent US10,472,664, November 12, 2019
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Inna Khartchenko, MS, MBA
Director, Technology Transfer and New Ventures