A potent inhibitor of Pim kinases
SGI-1776 free base, N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine, is a potent ATP-competitive inhibitor of the serine/threonine family of Pim kinase, an enzyme regulating cell survival. Through extensive biomedical characterization, SGI-1776 exhibits specificity to the three isoforms of the Pim family, including Pim-1, Pim-2, and Pim-3. According to preliminary results from studies treating prostate cancer cells, SGI-1776 dose-dependently reduces phosphorylation of known Pim kinase substrates involved in cell cycle progression and apotosis (p21Cip1/WAF1 and Bad), compromises overall cell viability by inducing G1 cell cycle arrest and triggering apoptosis, and reduces cell viability in a multidrug resistance 1 (MDR1) protein based taxane-refractory prostate cancer cell line.
Reference
[1].Shannon M. Mumenthaler, Patricia Y.B. Ng, Amanda Hodge, Davide Bearss, Gregory Berk, Sarath Kanekal, Sanjeev Redkar, Pietro Taverna, Davide B. Agus, and Anjali Jain. Pharmacological inhibition of Pim kinases alters prostate cancer cell growth and resensitizes chemoresistant cells to taxanes. Mol Cancer Ther. 2009; 8(10): 2882-2893
[2].Lisa S. Chen, S anjeev Redkar, David Bearss, William G. Wierda and Varsha Gandhi. Pim kinase inhibitor, SGI-1776, induces apoptosis in CLL lymphocytes. Blood. 2009; 114(19): 4150-4157
| Cell experiment: [1] | |
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Cell lines |
Primary lymphocytes from patients with CLL |
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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 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
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Reaction Conditions |
10 μM, 24 hours |
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Applications |
In vitro incubation of primary CLL cells with 1, 3, and 10 μM SGI-1776 for 24 hours resulted in an average increase in apoptosis of 10%, 22%, and 38%, respectively, compared with untreated cells. Incubation of CLL cells with SGI-1776 for 48 or 72 hours further increased the percentage of apoptotic cells. |
| Animal experiment: [2] | |
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Animal models |
Female BALB/c nude mice bearing 786-O or Caki-1 xenografts |
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Dosage form |
Oral administration, 200 mg/kg, once every 5 days, for 3 weeks |
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Applications |
Treatment with SGI-1776 resulted in a significant decrease in mean tumor volume in both xenograft models compared with the vehicle-treated controls. Besides that, SGI-1776 induced a reduction in Bad phosphorylation without altering total Bad protein levels. It also induced moderate levels of apoptosis. |
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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] Chen L S, Redkar S, Bearss D, et al. Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells. Blood, 2009, 114(19): 4150-4157. [2] Mahalingam D, Espitia C M, Medina E C, et al. Targeting PIM kinase enhances the activity of sunitinib in renal cell carcinoma. British journal of cancer, 2011, 105(10): 1563-1573. |
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