Abstract 2850: Talazoparib (BMN-673) possesses greater PARP1 trapping activity than structurally distinct PARP inhibitors with identical PARP1 binding properties

PARP1plays a central role in the repair of DNA damage. As such, PARP inhibitorsare currently undergoing clinical development as anti-cancer agents with a focus on tumors with impaired homologous recombination and on combination regimens containing DNA damaging chemotherapies or radiation. Pre-clinical data indicate that PARP inhibitorspotentiate the cytotoxicity of DNA alkylating agents in vitro and in vivo. Recent genetic and biochemical evidence indicates that one mechanism underlying this activity is the trapping of PARP1onto damaged chromatin. Strikingly, PARP inhibitorsthat differ by 10-fold in catalytic inhibition potency display up to a 10,000-fold difference in PARP1trapping activity in cells. This observation led to the proposal of an allosteric trapping mechanism; however, substantial biochemical and cellular data indicate that trapping is not allosteric in nature and is instead mediated by inhibition of automodification. Thus, it remains unclear why certain PARP inhibitorspossess such remarkable trapping activity in cells. The most potent trapping agent described to date is talazoparib. This compound is also among the most potent inhibitors of PARP catalytic activity and possesses a slow off-rate. In order to test the hypothesis that the potency and slow off-rate of talazoparibunderlie its potent trapping activity we sought to compare it to other compounds with similar biophysical properties. We have discovered a novel PARP inhibitor, A-934935, that binds to PARP1with affinity and kinetics nearly identical to talazoparib. Our data also reveal that rucaparibpossesses similar properties. Consistent with these similarities, all three agents inhibit PARP1with equal potency in enzyme activity assays and in cells. In addition, these compounds display identical trapping activity in a purified biochemical system. In contrast, talazoparibis a far more effective trapping agent than A-934935 or rucaparibin cells treated with MMS. High content imaging of gamma-H2Ax levels reveals that talazoparibpotentiates MMS-induced DNA damage more potently than rucaparibor A-934935. While this correlates with trapping activity, it remains unclear whether this relationship is causal. Investigation of this phenomenon is ongoing. These studies reveal that talazoparibpossesses trapping activity distinct from two other PARP inhibitorsof unrelated structure with identical PARP1binding properties. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Todd A. Hopkins, Yan Y. Shi, Enrico L. DiGiammarino, Sanjay C. Panchal, Gui-Dong G. Zhu, Thomas D. Penning, Eric F. Johnson, David Maag. Talazoparib(BMN-673) possesses greater PARP1trapping activity than structurally distinct PARP inhibitorswith identical PARP1binding properties. [ abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2850. doi:10.1158/1538-7445.AM2015-2850