KPT-6566
(Synonyms: 2-[[4-[[[4-(叔丁基)苯基]磺酰基]亚氨基]-1-氧代-1,4-二氢-2-萘基]硫基]乙酸) 目录号 : GC38577
KPT-6566 是一种有效、选择性、共价结合的脯氨酰异构酶 PIN1 抑制剂，与 PIN1 的催化位点共价结合，抑制并降解 PIN1。KPT-6566 对 PIN1 PPIase 结构域的 IC50 和 Ki 值分别为 640 nM 和 625.2 nM。KPT-6566 具有抗癌作用。
Cas No.:881487-77-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
MEF cells |
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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. |
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Reaction Conditions |
5 μM, 48h |
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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]: | |
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Animal models |
Nude mice |
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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. |
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Dosage form |
5 mg/kg, i.p. |
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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. |
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References: [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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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]
| Cas No. | 881487-77-0 | SDF | |
| 别名 | 2-[[4-[[[4-(叔丁基)苯基]磺酰基]亚氨基]-1-氧代-1,4-二氢-2-萘基]硫基]乙酸 | ||
| Canonical SMILES | O=C(O)CSC(C1=O)=C/C(C2=C1C=CC=C2)=N\S(=O)(C3=CC=C(C(C)(C)C)C=C3)=O | ||
| 分子式 | C22H21NO5S2 | 分子量 | 443.54 |
| 溶解度 | DMSO : 19.23 mg/mL (43.36 mM; Need ultrasonic) | 储存条件 | 4°C, protect from light, stored under nitrogen |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2546 mL | 11.2729 mL | 22.5459 mL |
| 5 mM | 0.4509 mL | 2.2546 mL | 4.5092 mL |
| 10 mM | 0.2255 mL | 1.1273 mL | 2.2546 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
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.PMID:32010480DOI:10.14336/AD.2019.0415.
Many oncogenes are involved in the progression from low-grade squamous intraepithelial lesions (LSILs) to high-grade squamous intraepithelial lesions (HSILs); which greatly increases the risk of cervical cancer (CC). Thus, a reliable biomarker for risk classification of LSILs is urgently needed. The prolyl isomerase Pin1 is overexpressed in many cancers and contributes significantly to tumour initiation and progression. Therefore, it is important to assess the effects of cancer therapies that target Pin1. In our study, we demonstrated that Pin1 may serve as a biomarker for LSIL disease progression and may constitute a novel therapeutic target for CC. We used a the novel Pin1 inhibitor KPT-6566, which is able to covalently bind to Pin1 and selectively target it for degradation. The results of our investigation revealed that the downregulation of Pin1 by shRNA or KPT-6566 inhibited the growth of human cervical cancer cells (CCCs). We also discovered that the use of KPT-6566 is a novel approach to enhance the therapeutic efficacy of cisplatin (DDP) against CCCs in vitro and in vivo. We showed that KPT-6566-mediated inhibition of Pin1 blocked multiple cancer-driving pathways simultaneously in CCCs. Furthermore, targeted Pin1 treatment suppressed the metastasis and invasion of human CCCs, and downregulation of Pin1 reversed the epithelial-mesenchymal transition (EMT) of CCCs via the c-Jun/slug pathway. Collectively, we showed that Pin1 may be a marker for the risk of progression to HSIL and that inhibition of Pin1 has anticancer effects against CC.
A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action
Nat Commun 2017 Jun 9;8:15772.PMID:28598431DOI:10.1038/ncomms15772.
The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening, we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells. Accordingly, KPT-6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo.
Inhibition of the PIN1-NRF2/GPX4 axis imparts sensitivity to cisplatin in cervical cancer cells
Acta Biochim Biophys Sin (Shanghai) 2022 Aug 25;54(9):1325-1335.PMID:35983979DOI:10.3724/abbs.2022109.
The incidence of cervical cancer (CC) ranks the fourth in female malignant tumors globally. Chemoresistance is one of the main causes of treatment failure in advanced recurrent CC. Prolyl isomerase 1 (PIN1) is overexpressed in a variety of tumors, and is closely associated with the malignant potential of tumor cells, such as transformation, proliferation, invasion and metastasis. In the present study, we demonstrate that cell death induced by suppression of PIN1 could be inhibited by ferrostatin-1 (Fer-1) and ferroptosis biomarkers including lactate dehydrogenase (LDH) release, lipid peroxidation and malondialdehyde (MDA) are upregulated by downregulating PIN1. We then discover that abrogation of PIN1 greatly decreases the level of glutathione peroxidase 4 (GPX4) and the level of PIN1 is positively correlated with the level of GPX4. Furthermore, the knockdown of PIN1 promotes ferroptosis induced by RSL3. The mechanism involves PIN1 silencing which downregulates GPX4 by decreasing the level of nuclear factor E2-related factor 2 (NRF2). Furthermore, overexpression of NRF2 inhibits RSL3-mediated ferroptosis of CC cells when PIN1 is silenced. In addition, our results indicate that cisplatin (DDP) induces ferroptosis, which is restrained by overexpression of PIN1. The PIN1 inhibitor, KPT-6566, promotes the cytotoxic effect of DDP. The present study reveals that PIN1 affects ferroptosis and sensitivity to DDP in CC cells via the NRF2/GPX4 axis, thereby identifying PIN1 as a potential therapeutic target for CC.