KPT-330|1393477-72-9|安捷凯

Background

KPT-330, analog of KPT-185, is a selective inhibitor of CRM1 [1].

Chromosomemaintenance protein 1 (CRM1) is a nuclear export receptor involved in the active transport of transcription factors, cell-cycle regulators, tumor suppressors and RNA molecules. In cancer, CRM1 is overexpression and overactive transport [1].

KPT-330 is an orally bioavailable and selective CRM1 inhibitor. In kidney cancer (RCC) cells, KPT-330 inhibited CRM1 and increased nuclear localization of p21. Then, KPT-330 induced apoptosis and inhibited cells growth [2]. In human non-small cell lung cancer (NSCLC) cells, KPT-330 inhibited cell proliferation and induced the expression of apoptosis-related proteins and cell cycle arrest [3].

In mice bearing MiaPaCa-2 xenograft model, KPT-330 (20 mg/kg) significantly inhibited tumor growth without significant toxicity or body weight loss. Also, KPT-330 increased PAR-4, pro-apoptotic Bax, cleaved PARP and caspase-3. These results suggested that KPT-330 induced apoptosis by the activation of PAR-4 signaling [1]. In mice bearing human NSCLC xenografts, KPT-330 significantly inhibited tumor growth [3].

参考文献:
[1].? Azmi AS, Aboukameel A, Bao B, et al. Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice. Gastroenterology, 2013, 144(2): 447-456.
[2].? Wettersten HI, Landesman Y, Friedlander S, et al. Specific inhibition of the nuclear exporter exportin-1 attenuates kidney cancer growth. PLoS One, 2014, 9(12): e113867.
[3].? Sun H, Hattori N, Chien W, et al. KPT-330 has antitumour activity against non-small cell lung cancer. Br J Cancer, 2014, 111(2): 281-291.

KPT-330 是 KPT-185 的类似物，是 CRM1 的选择性抑制剂 [1]。

染色体维持蛋白 1 (CRM1) 是一种核输出受体，参与转录因子、细胞周期调节因子、肿瘤抑制因子和 RNA 分子的主动转运。在癌症中，CRM1过度表达和过度活跃转运[1]。

KPT-330 是一种具有口服生物利用度的选择性 CRM1 抑制剂。在肾癌 (RCC) 细胞中，KPT-330 抑制 CRM1 并增加 p21 的核定位。然后，KPT-330 诱导细胞凋亡并抑制细胞生长 [2]。在人非小细胞肺癌（NSCLC）细胞中，KPT-330抑制细胞增殖并诱导凋亡相关蛋白的表达和细胞周期停滞[3]。

在携带 MiaPaCa-2 异种移植模型的小鼠中，KPT-330 (20 mg/kg) 显着抑制肿瘤生长，而没有明显的毒性或体重减轻。此外，KPT-330 增加了 PAR-4、促凋亡 Bax、裂解的 PARP 和 caspase-3。这些结果表明，KPT-330 通过激活 PAR-4 信号转导诱导细胞凋亡 [1]。在携带人 NSCLC 异种移植物的小鼠中，KPT-330 显着抑制肿瘤生长 [3]。

Protocol

Cell experiment [1, 2]:

Cell lines

NSCLC cells lines (A549, H460, H1975, PC14, H1299, and H23); MiaPaCa-2 and L3.6pl cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

1.0 μmol/L for 24h; or 0.1-1.0 μmol/L

Applications

KPT-330 inhibited proliferation, induced cell cycle arrest and apoptosis-related proteins in 11 NSCLC cells lines (A549, H460, H1975, PC14, H1299, and H23). Moreover, KPT-330 (0.1-1.0 μmol/L) dose-dependently inhibited the growth of MiaPaCa-2 and L3.6pl cells.

Animal experiment [1, 2]:

Animal models

Human NSCLC H1975 tumor xenograft model; human metastatic pancreatic cancer cells are orthotopically injected into the pancreas of mice model

Dosage form

10 mg/kg, oral treatment, thrice weekly for 4 weeks; or 10, 20 mg/kg p.o., 3/week

Applications

KPT-330(10 mg/kg) showed antitumour activity against human non-small cell lung cancer. Moreover, KPT-330 potentiated the antitumor activity of gemcitabine in human pancreatic cancer through inhibition of tumor growth, induction of apoptosis, and depletion of the antiapoptotic proteins.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

参考文献:

1. Sun, H., Hattori, N., Chien, W., Sun, Q., Sudo, M., GL, E. L., Ding, L., Lim, S. L., Shacham, S., Kauffman, M., Nakamaki, T. and Koeffler, H. P. (2014) KPT-330 has antitumour activity against non-small cell lung cancer. Br J Cancer. 111, 281-291

2. Kazim, S., Malafa, M. P., Coppola, D., Husain, K., Zibadi, S., Kashyap, T., Crochiere, M., Landesman, Y., Rashal, T., Sullivan, D. M. and Mahipal, A. (2015) Selective Nuclear Export Inhibitor KPT-330 Enhances the Antitumor Activity of Gemcitabine in Human Pancreatic Cancer. Mol Cancer Ther. 14, 1570-1581

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KPT-330

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