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-1 i.p) or the vehicle, after 27 days found that the metastatic growth in KPT-6566 treated animals was significantly reduced compared to controls.[2]
References:
[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.
KPT-6566 是一种新型 Pin1 特异性抑制剂。 KPT-6566 可以共价结合到它的催化位点并靶向 Pin1 进行降解。 KPT-6566 还能够特异性抑制 Pin1 过表达癌细胞的活力，而不影响正常细胞。[1] 此外，KPT-6566 对 HeLa 和 SiHa 细胞的 IC50 值为 13.5 和分别为 14.3 μM。 KPT-6566联合DDP处理组对HeLa/SiHa细胞凋亡率明显高于DDP组。[1]
体外实验表明，用2、4、6和8μM KPT-6566处理细胞可增强DDP对HeLa/SiHa细胞的杀伤作用。此外，用 5 μM KPT-6566 处理 Hela/SiHa 细胞，结果显示 Pin1 及其下游癌蛋白的丰度显着降低，包括 c-Jun、细胞周期蛋白 D1、β-catenin、ERK1/2、p- ERK、AKT 和 p-AKT473。[1]
KPT-6566 (5 mg/kg) 在体内抑制 CCC 的迁移和侵袭。体内实验表明，携带 60 mm3 肿瘤的小鼠用 20 mg/kg DDP、5 mg/kg KPT-6566、DDP 和 KPT-6566 的组合、单独的 KPT-6566 和 DDP 轻度抑制肿瘤生长裸鼠，而 KPT-6566 与 DDP 的组合显着抑制肿瘤生长。[1] 通过尾静脉注射 MDA-MB-231 细胞给裸鼠（15 只动物），然后在第二天癌细胞注射后，小鼠被随机分为两组，每天接受 KPT-6566（5 mg kg-1 i.p）或载体治疗，27 天后发现 KPT-6566 中的转移性生长与对照组相比，接受治疗的动物显着减少。[2]