American Association for Cancer Research, Molecular Cancer Therapeutics, 11_Supplement(12), p. CN05-01-CN05-01, 2013
DOI: 10.1158/1535-7163.targ-13-cn05-01
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Abstract Poly(ADPribose) polymerases (PARPs) are promising targets of several anticancer drugs in clinical development. We will review the genetic and biochemical evidence that PARP inhibitors act as cytotoxic anticancer agents by trapping PARP-DNA complexes (1). We will also show that PARP inhibitors differ from each other by their ability to trap PARP. They can be ranked by decreasing potency for PARP trapping: BMN-673 ≫ Niraparib > Olaparib = Rucaparib ≫ Veliparib, while all the PARP inhibitors are relatively similar with respect to PARP catalytic inhibition. We propose that PARP trapping results from allosteric effect whereas catalytic inhibition results from competition with NAD+. We will also discuss the rationale for combining PARP inhibitors with topoisomerase I inhibitors, and its dependence on PARP catalytic inhibition, and the rationale for combination with temozolomide, which depends both on catalytic inhibition and PARP trapping. 1. Murai J, Huang S-yN, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S, Pommier Y. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Research 2012; 72: 5588-99. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN05-01. Citation Format: Yves G. Pommier, Junko Murai, Joel Morris, James H. Doroshow. PARP inhibitors: Trapping of PARP and rational for combinations. [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 CN05-01.