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Discovery of potent 2,4-difluoro-linker poly(ADPribose) polymerase 1 inhibitors with enhanced water solubility and in vivo anticancer efficacy

   
@article{APS9681,
	author = {Wen-hua CHEN and Shan-shan SONG and Ming-hui QI and Xia-juan HUAN and Ying-qing WANG and Hualiang JIANG and Jian DING and Guo-bin REN and Ze-hong MIAO and Jian LI},
	title = {Discovery of potent 2,4-difluoro-linker poly(ADPribose) polymerase 1 inhibitors with enhanced water solubility and in vivo anticancer efficacy},
	journal = {Acta Pharmacologica Sinica},
	volume = {38},
	number = {11},
	year = {2017},
	keywords = {},
	abstract = {Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially in breast and ovarian cancers; tumor cells that are deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, we identified a series of 2,4-difluorophenyl-linker analogs (15−55) derived from olaparib as novel PARP1 inhibitors. Four potent analogs 17, 43, 47, and 50 (IC50=2.2−4.4 nmol/L) effectively inhibited the proliferation of Chinese hamster lung fibroblast V-C8 cells (IC50=3.2−37.6 nmol/L) in vitro, and showed specificity toward BRCA-deficient cells (SI=40−510). The corresponding hydrochloride salts 56 and 57 (based on 43 and 47) were highly water soluble in pH=1.0 buffered salt solutions (1628.2 μg/mL, 2652.5 μg/mL). In a BRCA1-mutated xenograft model, oral administration of compound 56 (30 mg·kg-1·d-1, for 21 d) exhibited more prominent tumor growth inhibition (96.6%) compared with the same dose of olaparib (56.3%); in a BRCA2-mutated xenograft model, oral administration of analog 43 (10 mg·kg-1·d-1, for 28 d) significantly inhibited tumor growth (69.0%) and had no negative effects on the body weights. Additionally, compound 56 exhibited good oral bioavailability (F=32.2%), similar to that of olaparib (F=45.4%). Furthermore, the free base 43 of the hydrochloride salt 56 exhibited minimal hERG inhibition activity (IC50=6.64 μmol/L). Collectively, these data demonstrate that compound 56 may be an excellent drug candidate for the treatment of cancer, particularly BRCA-deficient tumors.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/9681}
}