ABSTRACTCGK733 was reported as a compound that inhibited ATM/ATR kinase activities and blocked their checkpoint signaling pathways with great selectivity. However, this paper was subsequently retracted, and the truth about the activity of CGK733 remains unclear. We synthesized various analogs of CGK733 with a modification of the carboxylic acid moiety and/or the aniline derivative moiety to accumulate knowledge of the structure-activity relationship of this compound. Growth inhibitory activity of CGK733 and novel 35 analogs against HeLa S3 cells was evaluated, and the structure-activity relationship revealed that analogs with the 2-naphthyl or 4-fluorophenyl group instead of the benzhydryl group have activity comparable to CGK733 and that the 3-nitro group on the aniline moiety significantly affects the activity.

2023-10-01·iScience

CGK733 alleviates ovariectomy-induced bone loss through blocking RANKL-mediated Ca2+ oscillations and NF-κB/MAPK signaling pathways

Article

作者: Qin, Yiwu ; Huang, Jian ; Chen, Junchun ; Liu, Qian ; Wang, Chaofeng ; Xu, Jiake ; Xu, Minglian ; Su, Yuangang ; Song, Dezhi ; Zhao, Jinmin ; Xie, Xiaoxiao

Osteoporosis is a prevalent systemic metabolic disease in modern society, in which patients often suffer from bone loss due to over-activation of osteoclasts. Currently, amelioration of bone loss through modulation of osteoclast activity is a major therapeutic strategy. Ataxia telangiectasia mutated (ATM) inhibitor CGK733 (CG) was reported to have a sensitizing impact in treating malignancies. However, its effect on osteoporosis remains unclear. In this study, we investigated the effects of CG on osteoclast differentiation and function, as well as the therapeutic effects of CG on osteoporosis. Our study found that CG inhibits osteoclast differentiation and function. We further found that CG inhibits the activation of NFATc1 and ultimately osteoclast formation by inhibiting RANKL-mediated Ca²⁺ oscillation and the NF-κB/MAPK signaling pathway. Next, we constructed an ovariectomized mouse model and demonstrated that CG improved bone loss in ovariectomized mice. Therefore, CG may be a potential drug for the prevention and treatment of osteoporosis.

2022-01-01·International Endodontic Journal2区 · 医学

Effect of butyrate, a bacterial by‐product, on the viability and ICAM‐1 expression/production of human vascular endothelial cells: Role in infectious pulpal/periapical diseases

2区 · 医学

Article

作者: Wang, Tong‐Mei ; Chien, Hua‐Hong ; Chang, Mei‐Chi ; Jeng, Jiiang‐Huei ; Pan, Yu‐Hwa ; Jeng, Po‐Yuan ; Lin, Li‐Deh ; Tsai, Yi‐Ling

AbstractAimTo investigate the effects of butyric acid (BA), a metabolic product generated by pulp and root canal pathogens, on the viability and intercellular adhesion molecule‐1 (ICAM‐1) production of endothelial cells, which are crucial to angiogenesis and pulpal/periapical wound healing.MethodologyEndothelial cells were exposed to butyrate with/without inhibitors. Cell viability, apoptosis and reactive oxygen species (ROS) were evaluated using an MTT assay, PI/annexin V and DCF fluorescence flow cytometry respectively. RNA and protein expression was determined using a polymerase chain reaction assay and Western blotting or immunofluorescent staining. Soluble ICAM‐1 (sICAM‐1) was measured using an enzyme‐linked immunosorbent assay. The quantitative results were expressed as mean ± standard error (SE) of the mean. The data were analysed using a paired Student's t‐test where necessary. A p‐value ≤0.05 was considered to indicate a statistically significant difference between groups.ResultsButyrate (>4 mM) inhibited cell viability and induced cellular apoptosis and necrosis. It inhibited cyclin B1 but stimulated p21 and p27 expression. Butyrate stimulated ROS production and hemeoxygenase‐1 (HO‐1) expression as well as activated the Ac‐H3, p‐ATM, p‐ATR, p‐Chk1, p‐Chk2, p‐p38 and p‐Akt expression of endothelial cells. Butyrate stimulated ICAM‐1 mRNA/protein expression and significant sICAM‐1 production (p < .05). Superoxide dismutase, 5z‐7oxozeaenol, SB203580 and compound C (p < .05), but not ZnPP, CGK733, AZD7762 or LY294002, attenuated butyrate cytotoxicity to endothelial cells. Notably, little effect on butyrate‐stimulated sICAM‐1 secretion was found. Valproic acid, phenylbutyrate and trichostatin (three histone deacetylase inhibitors) significantly induced sICAM‐1 production (p < .05).ConclusionButyric acid inhibited proliferation, induced apoptosis, stimulated ROS and HO‐1 production and increased ICAM‐1 mRNA expression and protein synthesis in endothelial cells. Cell viability affected by BA was diminished by some inhibitors; however, the increased sICAM‐1 secretion by BA was not affected by any of the tested inhibitors. These results facilitate understanding of the pathogenesis, prevention and treatment of pulpal/periapical diseases.

100 项与 CGK733 相关的药物交易

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