PARP Inhibitor and NO-Donor Dual Prodrugs as Anticancer Agents

Poly-ADP ribose polymerase-1 (PARP-1) is a critical enzyme involved in DNA repair.  The inhibition of PARP has emerged as a promising strategy in cancer therapy.  Numerous PARP inhibitors have been developed and advanced into clinical trials, both for use as single agents in specific patient populations and as combination therapies with various chemotherapeutics.  The induction of strand break damage to DNA, as has been demonstrated in cancer cells treated with O2-arylated diazeniumdiolates, coupled with inhibition of DNA repair by PARP inhibitors, represents a novel rationale for effective combination therapy.

Scientists at NCI developed prodrugs that combine structural features of the known PARP inhibitor olaparib  with an O2-arylated diazeniumdiolate in one hybrid molecule.  The two-component prodrug has the advantage of delivering both a DNA damaging agent (NO) and an inhibitor of DNA repair (PARP inhibitor) simultaneously to a cancer cell.  The prodrugs are activated by glutathione (GSH) and the reaction accelerated by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancer.  This mechanism consumes GSH while releasing cytotoxic NO and a PARP inhibitor simultaneously in the target cancer cell.  As high levels of GSH/GSTP1 are often a feature of cancer cells, the compound is predicted to have strong synergy with other anticancer therapeutics. When compared to the PARP inhibitor olaparib, these hybrid molecules exceeded the in vivo anticancer potency in xenograft models, resulting in more extensive DNA strand break damage, and ultimately greater apoptosis induction, as observed in vitro. These compounds are predicted to have strong radio- and chemosensitizing effects.

Competitive Advantages:

• Combination of a DNA damaging agent and a DNA repair inhibitor in one molecule eliminates the need to administer two separate treatments;
• Activation mechanism that involves overexpressed in cancers GSTP1 targets drugs to cancer cell

Commercial Applications:

• Stand-alone cancer therapeutics or as part of a combination therapy with other cancer therapies