P276-00 (P276-00) 是一种有效的细胞周期蛋白依赖性激酶 (CDK) 抑制剂，可抑制 CDK9-cyclinT1、CDK4-cyclin D1 和 CDK1-cyclinB，IC50 分别为 20 nM、63 nM 和 79 nM。 P276-00 (P276-00) 对顺铂耐药细胞具有抗肿瘤活性。
P276-00 is a novel inhibitor for CDK-1, CDK4 and CDK9 with IC50 of 79 nM, 63 nM and 20 nM, respectively [1].
CDK (cyclin-dependent kinase) plays an important role in cell cycle progression via promoting the G1/S cell cycle transition. Many studies have shown that more CDKs are overexpressed in cancer cells than in normal cells, which explain the reason of cancer cells divide uncontrollably[2]. The overexpression of CDK1/4/6 contributes to the phosphorylation of retinoblastoma protein (RB) via binding to CCND1 and results in the release of E2F transcription of genes required for cell cycle progression [3].
P276-00 is a novel inhibitor of CDK (cyclin-dependent kinase) with the ability of arresting the cells in G1/S phase transcription. When tested with NSCLC cell lines, P276-00 showed high ability of inhibiting cell proliferate thus decreased the colony forming potential via blocking cell cycle [4]. In head and neck squamous carcinoma cell line (FaDu, Detroits-562, SCC-25), treated with P276-00 for 12 hours could significantly inhibit cell ability with IC50 value ranging from 0.8 to 1.7 uM for different cell lines via decreasing the expression of CCND1[2].
In SCID mice model with H460 xenograft, treatment of P276-00 could down regulate the expression of CDK1 thus induced tumor regression [4]. When tested with HNSCC tumor xenograft mouse model, P276-00 treatment showed anti-cancer ability with a 48% tumor growth inhibition [2].
参考文献:
1.Manohar, S.M., et al., Cyclin-dependent kinase inhibitor, P276-00 induces apoptosis in multiple myeloma cells by inhibition of Cdk9-T1 and RNA polymerase II-dependent transcription. Leuk Res, 2011. 35(6): p. 821-30.
2.Mishra, P.B., et al., Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma. J Transl Med, 2013. 11(42): p. 1479-5876.
3.Raje, N., et al., Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma. Leukemia, 2009. 23(5): p. 961-70.
4.Shirsath, N., et al., Potentiation of anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the cyclin-dependent kinase inhibitor P276-00 in human non-small-cell lung cancer cell lines. Lung Cancer, 2013. 82(2): p. 214-21.
| 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 | |
动态评分
0.0