Abstract A121: Novel PARP inhibitors with potent antitumor activity as single-agent and combination therapies

Abstract

Abstract Poly (ADP-ribose) polymerases (PARP) -1 and -2 are key enzymes that are activated by DNA damage and play a critical role in the base excision DNA repair (BER) pathway. Previous studies have indicated that inhibitors of PARP-1 and -2 could enhance the efficacy of radiation therapy and chemotherapies by preventing cancer cells from repairing DNA damage. In addition, PARP inhibitors have been shown to selectively kill cancer cells that are deficient in BRCA-1 or BRCA-2 function. In this study, we describe the antitumor activity of a series of novel PARP inhibitors in single-agent therapy and in combination with standard chemotherapies. One of the compounds in this series, LT-00673, inhibits PARP-1 with IC50 at sub-nanomolar (nM) concentration. In cultured human cancer cells, LT-00673 significantly enhances the cytotoxic efficacy of both Temozolomide and SN-38 (active metabolite of Irinotecan). LT-00673 also demonstrates single-agent cytotoxicity in BRCA-1 mutant (MX-1, IC50 = 0.3 nM) and BRCA-2 mutant cells (Capan-1, IC50 = 5 nM). In contrast, in MRC-5 normal human fibroblast and other tumor cell lines with wild-type BRCA-1 and BRCA-2 genes, IC50 of LT-00673 ranges between 90 nM and 1.9 µM. In rat pharmacokinetic studies, LT-00673 displays >50% oral bioavailability and pharmacokinetic properties that enable single daily dosing. In xenograft tumor model studies, daily oral dosing of LT-00673 significantly enhances the antitumor effects of cytotoxic therapies in a dose-dependent manner. In addition, once daily oral dosing of LT-00673 at 0.33 mg/kg/day results in complete response in the MX-1 tumor model. Pharmacodynamic studies have demonstrated potent PARP inhibition by LT-00673 in tumor biopsies. Off-target molecular screening did not identify significant non-specific activity for this class of PARP inhibitors. In summary, LT-00673 displays potent antitumor activity, along with oral bioavailability and pharmacokinetic properties that support in vivo efficacy on single daily doses, both as single-agent therapy and in combination with cytotoxic chemotherapies. Conclusion: LT-00673 shows promising in vitro and in vivo activities and is currently in preclinical development. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A121.