Abstract A257: Stereospecific trapping of PARP-DNA complexes by BMN 673 and comparison with olaparib and rucaparib.

Abstract

Abstract Anti-poly(ADP-ribose)polymerase (PARP) drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. Yet, several PARP inhibitors have an additional cytotoxic mechanism by trapping PARP-DNA complexes; both olaparib and niraparib act as PARP poisons at pharmacological concentrations (Murai et al., Cancer Res, 2012). Here, we evaluate the novel PARP inhibitor, BMN 673, and compare its effects on PARP1 and PARP2 with two other clinical PARP inhibitors, olaparib and rucaparib, using biochemical and cellular assays in genetically-modified chicken DT40 and human cancer cell lines. We show that BMN 673, olaparib, and rucaparib are similarly potent at inhibiting PARP catalytic activity. At the same time, BMN 673 is ∼100-fold more potent at trapping PARP-DNA complexes and more cytotoxic as a single agent than olaparib, while olaparib and rucaparib show similar potencies in trapping PARP-DNA complexes. The high level of resistance of PARP1/2 knockout cells to BMN 673 demonstrates the selectivity of BMN 673 for PARP1/2. Moreover, we show that BMN 673 acts by stereospecific binding to PARP1 as its enantiomer, LT674, is several orders of magnitude less efficient, and that BMN 673 is more cytotoxic than olaparib and rucaparib in combination with the DNA alkylating agents methyl methane sulfonate (MMS) and temozolomide. Our study demonstrates that BMN 673 is the most potent clinical PARP inhibitor to date with the highest efficiency at trapping PARP-DNA complexes. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A257. Citation Format: Junko Murai, Shar-yin N. Huang, Amelie Renaud, Yiping Zhang, Jiuping Ji, Shunichi Takeda, Joel Morris, Beverly Teicher, James H. Doroshow, Yves Pommier. Stereospecific trapping of PARP-DNA complexes by BMN 673 and comparison with olaparib and rucaparib. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A257.