A potent pan-PI3K and mTOR inhibitor
GSK2126458 is an inhibitor of PI3K/mTOR with Ki value of 19 pM for PI3K [1].
PI3K (phosphoinositide 3-kinase) plays an important role in regulating cell growth and transformation, and mTOR (mammalian target of rapamycin) which works as a class IV PI3K protein kinase, is also a crucial regulator of cell growth [2]. It has been shown that up-regulation of PI3K/mTOR (phosphatidylinositol-3' kinase/mammalian target of rapamycin) signaling is widespread in carcinoma which may be worked as a biomarker used in clinic [3].
GSK2126458 is a highly potent inhibitor of PI3K/mTOR. When subjected to colorectal cancer cell lines, GSK2126458 could potentiate the cells antiproliferative activity via combining with DDR1-IN-1[4]. In BT474 breast cancer lines, treated with GSK2126458 could be the arrest of G1 cell cycle and thus inhibit cell proliferation [5]. GSK2126458 also could improve the sensitivity of NPC cells to radiation and suppress tumor progression [1]. ?
In a 5-8F xenograft model with NPC, treated the mouse with GSK2126458 combining of IR significantly inhibited the tumor growth [1]. In mice injected with cancer cells from melanoma patient resisted to the combination of divergent and trametinib, GSK2126458 combined with dabrafenib, trametinib treatment resulted in sustained inhibition of tumor growth[3].
GSK2126458 may play a significant role in regulating autophagy [6].
参考文献:
1.Liu, T., et al., Dual PI3K/mTOR inhibitors, GSK2126458 and PKI-587, suppress tumor progression and increase radiosensitivity in nasopharyngeal carcinoma. Mol Cancer Ther, 2014. 12.
2.Simpson, D.R., L.K. Mell, and E.E. Cohen, Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck: Oral Oncol. 2014 Dec 17. pii: S1368-8375(14)00351-0. doi: 10.1016/j.oraloncology.2014.11.012.
3.Villanueva, J., et al., Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep, 2013. 4(6): p. 1090-9.
4.Kim, H.G., et al., Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor. ACS Chem Biol, 2013. 8(10): p. 2145-50.
5.Knight, S.D., et al., Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. ACS Med Chem Lett, 2010. 1(1): p. 39-43.
6.Zhang, Y., et al., Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways. Mol Med Rep, 2014. 9(1): p. 83-90.
| Cell experiment [1]: | |
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Cell lines |
NPC cell lines (CNE-2, 5-8F, and 6-10B) |
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Preparation method |
The solubility of this compound in DMSO is >25.3mg/mL. 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. |
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Reacting condition |
0.003 mmol/L |
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Applications |
GSK2126458 decreased the viability of NPC cells at low nanomolar concentrations and in a concentration- and time-dependent manner. GSK2126458 inhibited migration and invasion of NPC cells. Treatment with GSK2126458 led to an increased percentage of cells in G1 phase. |
| Animal experiment [1]: | |
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Animal models |
Female BALB/c-nu/nu nude mice bearing 5-8F cells |
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Dosage form |
300 μg/kg, Intragastric administration once daily for 5 consecutive days each week. |
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Application |
The combination of IR with GSK2126458 resulted in >50% reduction in xenograft volume and tumor regrowth delay. Treatment with GSK2126458 or PKI-587 alone slightly inhibited tumor growth. |
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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. |
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参考文献: [1]. Liu T, Sun Q, Li Q, et al. Dual PI3K/mTOR inhibitors, GSK2126458 and PKI-587, suppress tumor progression and increase radiosensitivity in nasopharyngeal carcinoma[J]. Molecular cancer therapeutics, 2015, 14(2): 429-439. | |
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