Abstract 691: In vitro and in vivo characterization of selective orally available Parp-1 inhibitors with demonstrated antitumor efficacy in BRCA negative cancer models

Poly (ADP-ribose) polymerase 1 and 2 (Parp-1 and Parp-2) are nuclear enzymes responsible for signaling the presence of DNA damages by catalyzing the addition of ADP-ribose units to DNA, histones and various DNA repair enzymes, thus facilitating DNA repair. Parp-1 has been gaining increasing interest as a therapeutic target for cancer in combination with DNA damaging agents but also as single agent in particular tumor settings, such as BRCA mutated tumors. While Parp-1 knock out mice are viable and display only defects in DNA repair, double Parp-1 and Parp-2 knock-out are embryonic lethal indicating that the absence of Parp-1 and Parp-2 is less tolerated in normal cells. We confirmed this concept in vitro by RNAi of Parp-1 and Parp-2, showing that the inhibition of Parp-1 alone is enough to kill tumor cells but spares normal cells. Hence a selective Parp-1 inhibitor might have a better safety profile, particularly in view of a long treatment. Here we report the discovery and the in vitro and in vivo characterization of a novel class of potent, orally available Parp-1 selective small molecule inhibitors with no activity on other Parp isoforms such as Parp-2, −3 and −5a (tankyrase), which differentiates it from current clinical Parp inhibitors. The most potent compounds were further evaluated in vitro and in vivo. These compounds are highly potent in inhibiting DNA damage-induced Parp-1 activity in cells and exhibit selective anti-proliferative and pro-apoptotic activity in tumor cell lines harbouring defects in DNA repair. In vivo, the compounds show an excellent pharmacokinetic profile with almost complete oral bioavailability and demonstrate efficacy as a single agent in xenograft tumor models with DNA repair deficiencies superior to reference Parp inhibitors. These compounds are very well tolerated with no overt toxicity even after prolonged exposure and their mechanism of action is confirmed both in tumors and peripheral blood cells of treated mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 691.