Original Article

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

Authors: CHEN Wen-hua, SONG Shan-shan, QI Ming-hui, HUAN Xia-juan, WANG Ying-qing, JIANG Hualiang, DING Jian, REN Guo-bin, MIAO Ze-hong, LI Jian
Corresponding to: CHE Wen-hua
DOI: 10.1038/aps.2017.104


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.
Keywords: PARP-1 inhibitor; olaparib; breast cancer; BRCA-deficient tumors