规格: | 98% |
分子量: | 443.54 |
Background:
KPT-6566 is a novel Pin1-specific inhibitor. KPT-6566 covalently can bind to the catalytic site of it and targets Pin1 for degradation. KPT-6566 is also able to specifically inhibit the vitality of Pin1-overexpressing cancer cells while not affecting normal cells.[1]Moreover, the IC50 values of KPT-6566 for HeLa and SiHa cells were 13.5 and 14.3 μM, respectively. Combination KPT-6566 with DDP treatment group was obiviously higher than that observed in the DDP group in terms of the apoptosis rate of HeLa/SiHa cells.[1]
In vitro experiment it shown that treatment with 2, 4, 6 and 8 μM KPT-6566 of cells enhanced the killing effect of HeLa/SiHa cells by DDP. In addition, treatment with 5 μM KPT-6566 of Hela/SiHa cells, the results exhibited a significant decrease in the abundance of Pin1 and its downstream oncoproteins, including c-Jun, cyclin D1, β-catenin, ERK1/2, p-ERK, AKT, and p-AKT473.[1]
KPT-6566 (5 mg/kg) inhibited the migration and invasion of CCCs in vivo. In vivo experiment it demonstrated that the mice carried 60 mm3 tumor were treated with 20 mg/kg DDP, 5 mg/kg KPT-6566, a combination of DDP and KPT-6566, KPT-6566 and DDP alone mildly inhibited the tumour growth in nude mice, whereas the combination of KPT-6566 with DDP significantly inhibited tumour growth.[1]By tail vein injection of MDA-MB-231 cells in nude mice (15 animals), then the day after cancer cell injection, mice were randomized in two groups to be treated daily with either KPT-6566 (5?mg?kg-1i.p) or the vehicle, after 27 days found that the metastatic growth in KPT-6566 treated animals was significantly reduced compared to controls.[2]
参考文献:
[1].Guo YT, et al. Predictive Value of Pin1 in Cervical Low-Grade Squamous Intraepithelial Lesions and Inhibition of Pin1 Exerts Potent Anticancer Activity against Human Cervical Cancer. Aging Dis. 2020 Feb 1;11(1):44-59.
[2].Campaner E, et al. A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action. Nat Commun. 2017 Jun 9;8:15772.
Protocol:
Cell experiment [1]: | |
Cell lines | MEF cells |
Preparation Method | Growth curves of WT or Pin1 KO MEFs treated with the indicated concentrations of KPT-6566 (5?μM) or DMSO. Immunoblotting of the indicated cell cycle-related proteins in WT or Pin1 KO MEFs treated with 5?μM KPT-6566 (+) or DMSO (?) for 48?h. |
Reaction Conditions | 5?μM, 48h |
Applications | In WT MEFs KPT-6566 had a negative, dose-dependent effect on proliferation and induced a decrease of hyperphosphorylated pRB and Cyclin D1 levels. |
Animal experiment [2]: | |
Animal models | Nude mice |
Preparation Method | When the tumour volumes reached 60 mm3, the mice were randomly grouped into four groups and treated with 20 mg/kg DDP, 5 mg/kg KPT-6566, a combination of DDP and KPT-6566 or a saline vehicle. |
Dosage form | 5 mg/kg, i.p. |
Applications | KPT-6566 and DDP alone mildly inhibited the tumour growth in nude mice, whereas the combination of KPT-6566 with DDP significantly inhibited tumour growth. |
参考文献: [1]. Campaner E, et al. A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action. Nat Commun. 2017 Jun 9;8:15772. [2]. Guo YT, et al. Predictive Value of Pin1 in Cervical Low-Grade Squamous Intraepithelial Lesions and Inhibition of Pin1 Exerts Potent Anticancer Activity against Human Cervical Cancer. Aging Dis. 2020 Feb 1;11(1):44-59. |
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