Abstract B64: Structure and preclinical characterization of BMN 673, a potent and orally active PARP inhibitor as an anticancer agent.

Abstract

Abstract In this presentation we will present the chemical structure, biological activity and pharmacokinetic (PK) properties of BMN 673, a potent inhibitor of poly (ADP-ribose) polymerases (PARP)-1 and -2. PARP-1 and -2 are key nuclear enzymes that are activated by DNA damage and play a critical role in the base excision DNA repair (BER) pathway. Inhibitors of PARP-1 and -2 could enhance the cytotoxicity of DNA damaging agents by preventing cancer cells from repairing DNA damage. In addition, PARP inhibitors have been shown to selectively kill cancer cells that are deficient in BRCA-1 or BRCA-2 function. A previously unexplored chemical scaffold was discovered with good PARP inhibitory activity. Optimization of this scaffold produced BMN 673, the most potent PARP inhibitor reported to date. BMN 673 selectively kills cancer cells with BRCA-1 or BRCA-2 mutations. In xenograft tumor model studies, oral dosing of BMN 673 results in complete regression of the BRCA-deficient tumors. In addition to BRCA-1/2 mutations, we examined the correlation of other DNA repair defects with the tumor cells' sensitivity to BMN 673 treatment. We show that tumor cells with PTEN mutation are highly sensitive to BMN 673 treatment in vitro. Xenograft tumor models that harbor PTEN deficiency responded to oral BMN 673 treatment with significant tumor growth delay. Deficiencies in ATM and other homologous recombination (HR) DNA repair genes, as well as unidentified genetic deficiencies, result in sensitivity to cell killing by BMN 673 in head-and-neck cancer, myeloma, and mantle cell lymphoma. These results suggest that BMN 673 may be a valid treatment option for cancers with these genetic defects. In animal PK/PD studies, BMN 673 displays good oral bioavailability and PK properties, and demonstrates significant in vivo PARP inhibition in xenograft tumors and other tissues. BMN 673 is currently in phase 1 clinical trials in patients with solid tumors or hematological malignancies. 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 B64.