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

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.

• Authors: Wen-Hua Chen, Shan-Shan Song, Ming-Hui Qi, Xia-Juan Huan, Ying-Qing Wang, Hualiang Jiang, Jian Ding, Guo-Bin Ren, Ze-Hong Miao, Jian Li
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 38 Issue 11 Pg. 1521-1532 (Nov 2017) ISSN: 1745-7254 [Electronic] United States
• PMID: 28770827 (Publication Type: Journal Article)

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• BRCA2 Protein
• BRCA2 protein, human
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• Water
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• olaparib

Topics

• Administration, Oral
• Animals
• BRCA1 Protein (genetics)
• BRCA2 Protein (genetics)
• Biological Availability
• Breast Neoplasms (drug therapy, enzymology, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cricetulus
• Dose-Response Relationship, Drug
• Drug Discovery (methods)
• Female
• Humans
• Inhibitory Concentration 50
• Injections, Intravenous
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Structure
• Phthalazines (chemistry, pharmacology)
• Piperazines (chemistry, pharmacology)
• Poly (ADP-Ribose) Polymerase-1 (antagonists & inhibitors, metabolism, pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors (chemistry, pharmacokinetics, pharmacology)
• Rats, Sprague-Dawley
• Solubility
• Structure-Activity Relationship
• Tumor Burden
• Water (chemistry)
• Xenograft Model Antitumor Assays