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.
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Acknowledgements
Financial support of this research was provided by the National Natural Science Foundation of China (Grants 21672064, 8152200403 and 21372001), the “Shu Guang” Project supported by the Shanghai Municipal Education Commission and the Shanghai Education Development Foundation (Grant 14SG28), the Science and Technology Commission of Shanghai Municipality (No 15431901200), and the Fundamental Research Funds for the Central Universities.
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Chen, Wh., Song, Ss., Qi, Mh. et al. Discovery of potent 2,4-difluoro-linker poly(ADP-ribose) polymerase 1 inhibitors with enhanced water solubility and in vivo anticancer efficacy. Acta Pharmacol Sin 38, 1521–1532 (2017). https://doi.org/10.1038/aps.2017.104
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DOI: https://doi.org/10.1038/aps.2017.104
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