Abstract C179: Discovery of a series of novel PARP-1 inhibitors with potent in vitro and in vivo activity.

Poly (ADP-ribose) polymerase (PARP) catalyzes the addition of poly (ADP-ribose) to target proteins that is an important process in DNA repair. PARP-1 inhibitors are expected to increase the therapeutic efficacy of DNA damaging anticancer agents, and are cytotoxic to BRCA1 or BRCA2 deficient cancer cells. Recently, phase II clinical trial data have shown that PARP-1 inhibitor olaparib (AZD2281) was effective in the treatment of advanced breast cancer. Hopefully the discovery and development of novel and potent PARP-1 inhibitors will lead to a new class of anticancer drugs. In this presentation, we will report the discovery of a series of novel and potent PARP-1 inhibitors. We have found more than 40 compounds that are several folds more potent than AZD2281 in multiple in vitro assays. Several of these compounds have excellent oral bioavailability (F values approaching 50%) and low toxicity (well tolerated when dosed orally up to 100 mg/kg once a day for 5 days). Two lead compounds have been tested in animal efficacy animal models and found to be 10–20 folds more efficacious than AZD2281. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C179.