Abstract A221: Novel PARP6 inhibitors demonstrate in vivo efficacy in xenograft models.

The poly (ADP-ribose) polymerase (PARP) family of enzymes are functionally implicated in DNA repair, transcriptional regulation, glucose metabolism, mitosis, and other cellular mechanisms. To date, the focus has been on defining the role of PARPs 1-3 in DNA damage repair. Currently, PARP1-3 inhibitors are in clinical trials for BRCA1/2 mutant ovarian and breast cancers. The roles of other PARP family members are starting to emerge. Using a cell-based assay measuring multi-polar spindle induction, PARP6 was identified as novel target with therapeutic potential. AZ482 and AZ108 were developed as potent PARP6 inhibitors. These compounds exhibited a unique and selective growth inhibition profile when screened in large panels of tumor cells and suitable pharmacokinetics in vivo. In sensitive hematological and solid tumor models, these compounds had low nanomolar potency in vitro and anti-tumor efficacy in vivo. Mechanistic studies suggest PARP6 inhibitors disrupt spindle pole clustering resulting in mitotic catastrophe and may show selectivity toward tumor cell lines with supernumary centrosomes. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A221. Citation Format: Michele F. Mayo, Shaun Grosskurth, Xin Wang, Philip Petteruti, Prasad Nadella, Corinne Reimer, Keith Mikule. Novel PARP6 inhibitors demonstrate in vivo efficacy in xenograft models. [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 A221.