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

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) fo...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2015-08, Vol.75 (15_Supplement), p.1643-1643
Hauptverfasser: Cai, Sui Xiong, Xu, Qingbing, Wu, Lizhen, Yin, Feng, Hu, Xiuhua, Wang, Xiaozhu, Jiang, Yangzhen, Bao, Qingli, Wang, Guoxiang, Zhang, Xiuyan, Tian, Ye Edward
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Sprache:eng
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Zusammenfassung: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
ISSN:0008-5472
1538-7445
DOI:10.1158/1538-7445.AM2015-1643