A selective ALK inhibitor
TAE684 (NVP-TAE684) is a selective inhibitor of ALK with IC50 value of 3 nM [1].
Anaplastic lymphoma kinase?(ALK) is an enzyme and plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. It has been reported that ALK involves in the pathogenesis of various cancers and serves as an important therapeutic target [1, 2].
TAE684 (NVP-TAE684) is a potent ALK inhibitor and has a different selectivity with the reported ALK inhibitor crizotinib. When tested with ALCL cell lines—Karpas-299 and SU-DHL-1 expressing NPM-ALK, TAE684 (NVP-TAE684) inhibited cell proliferation and cell apoptosis in dose-dependent manner [1]. In lung cancer cell lines harboring wild-type, H694R or E1384K mutant ALKs, TAE684 showed effective inhibition on cell proliferation and phospho-Y1604 ALK expression of H694R or E1384K mutant ALK, but also to a degree higher than that of wild-type ALK [2].
In SCIDbeige mice model with luciferized Karpas-299 cells subcutaneous xenograft, in which the invasion could be detected by a strong bioluminescence signal, oral administration of TAE684 (NVP-TAE684) caused significant reduction of lymphoma develop and 100- to 1000-fold reduction in luminecsene signal at the dose of 3 and 10 mg/kg. And, the group received TAE684 (NVP-TAE684) at the dose of 10 mg/kg appeared healthy and showed no signs of compound- or disease-related toxicity [1].
It is also reported that TAE684 is a potent inhibitor of leucine-rich repeat kinase 2 (LRRK2) with IC50 value of 7.8 nM [3].
参考文献:
[1].? Galkin, A.V., et al., Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Acad Sci U S A, 2007. 104(1): p. 270-5.
[2].? Wang, Y.W., et al., Identification of oncogenic point mutations and hyperphosphorylation of anaplastic lymphoma kinase in lung cancer. Neoplasia, 2011. 13(8): p. 704-15.
[3].? Zhang, J., et al., Characterization of TAE684 as a potent LRRK2 kinase inhibitor. Bioorg Med Chem Lett, 2012. 22(5): p. 1864-9.
| Cell experiment: [1] | |
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Cell lines |
Ba/F3 and Ba/F3 NPM-ALK cells |
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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 |
50 nM, 48 hours |
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Applications |
Cells were treated with various concentrations of TAE684 for 72 h and were assessed for induction of apoptosis and growth arrest by f low cytometry every 24 h. Treatment with TAE684 increased the number of Annexin V-positive Ba/F3 NPM-ALK cells in a dose- and time-dependent manner, without affecting the survival of the parental Ba/F3 cell line. At 48 h after incubation with TAE684, 85–95% of cells stained Annexin V-positive in several independent experiments. In contrast, no increase in the number of Annexin V-positive cells was seen for parental Ba/F3 cells grown in the presence of IL-3. |
| Animal experiment: [1] | |
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Animal models |
SCIDbeige mice injected with Karpas-299-luc cells |
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Dosage form |
Oral administration; 1, 3, and 10 mg/kg; once daily |
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Applications |
After 2 weeks of treatment, we observed a 100-fold reduction in bioluminescence signal in the 3- and 10-mg/kg treatment groups. Although the compound was not efficacious at 1 mg/kg, after 4 weeks of treatment with TAE684 at 3 and 10mg/kg, there was a significant delay in lymphoma development and 100- to 1,000-fold reduction in luminescence signal. The TAE684- (10mg/kg) treated group appeared healthy and did not display any signs of compound- or disease-related toxicity. |
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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] Galkin A V, Melnick J S, Kim S, et al. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proceedings of the National Academy of Sciences, 2007, 104(1): 270-275. | |
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