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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-difluorcphenyl-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·kg1·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·kg1·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.