Abstract 1643: Discovery of 1-benzylquinazoline-2,4(1H,3H)-diones as novel and potent PARP inhibitors. SAR of the benzyl group

Abstract Poly (ADP-ribose) polymerase (PARP) is a key enzyme for DNA repair and PARP-1 inhibitors have been shown to be effective against cancers with DNA repair defects, such as BRCA1 or BRCA2 mutations. Recently, European Medicines Agency (EMA) recommended approval of PARP-1 inhibitor Olaparib (AZD2281) for the treatment of ovarian cancers with BRCA mutations. In this presentation, we will report our discovery of a series of 1-benzylquinazoline-2,4(1H,3H)-diones (BQD) as novel and potent PARP inhibitors. We will present SAR data for substituents at the 3- and 4-positions of the benzyl group of BQD, and the identification of IMP4297 as a clinical candidate. IMP4297 has advantages in vitro and in vivo over AZD2281. It is not only more potent but also more selective than AZD2281 in cell-based assays, and was 20-fold more efficacious than AZD2281 in a BRCA1 mutated MDA-MB-436 human breast cancer xenograft model. IND enabling studies for IMP4297 is in progress with IND submission planned in 12 months. Citation Format: Sui Xiong Cai, Qingbing Xu, Lizhen Wu, Feng Yin, Xiuhua Hu, Xiaozhu Wang, Yangzhen Jiang, Qingli Bao, Guoxiang Wang, Xiuyan Zhang, Ye Edward Tian. Discovery of 1-benzylquinazoline-2,4(1H,3H)-diones as novel and potent PARP inhibitors. SAR of the benzyl group. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1643. doi:10.1158/1538-7445.AM2015-1643