A cell-permeable FLT3 inhibitor
TCS 359 is a potent inhibitor against the fms-like tyrosine kinase-3 (FLT3) [1] [2] with an IC50 value of 0.042 ±0.03 μM [2].
FLT3 is a receptor tyrosine kinase. Via hematopoietic regulation, it plays its important role in the pathogenesis of acute myeloid leukemia (AML) [3].
To the proliferation of MV4-11 cell line (a human acute myeloid leukemia cell line expressing a constitutively activated mutant FLT3), the IC50 of TCS 359 was 0.34 μM [2].
TCS 359 blocked the ability of FLT3 ligand to promote the development of two-cell-embryos to the hatched blastocyst stage in mice. TCS 359 also decreased the expression of FLT3 ligand in early embryos after the four-cell stage. Without exogenous FLT3 ligand, TCS 359 did not affect embryo development [4]. Treated with another FLT3 inhibitor SU5416, 21 of 22 analyzed patients expressed FLT3 protein, 17 expressed phosphorylated FLT3 at baseline. Among these 17 patients expressed phosphorylated FLT3, inhibition of more than 50% relative to baseline was apparent in seven cases, while inhibition ranged from 20-50% relative to baseline was apparent in an additional three cases. FLT3 phosphorylation was detected in whole blood lysates in the majority of AML patients treated with SU5416. Activated FLT3 was detectable in bone marrow aspirates from approximately 50% AML patients [5].
参考文献:
[1].? Trzci′nska-Daneluti A.M., Nguyen L., Jiang C., et al. Use of Kinase Inhibitors to Correct ΔF508-CFTR Function. Molecular & Cellular Proteomics, 2012, 11(9):745-757.
[2].? Patch R.J., Baumann C.A., Liu J., et al. Identification of 2-acylaminothiophene-3-carboxamides as potent inhibitors of FLT3. Bioorganic & Medicinal Chemistry Letters, 2006, 16: 3282-3286.
[3].? Kar R.K., Suryadevara P., Roushan R., et al. Quantifying the Structural Requirements for Designing Newer FLT3 Inhibitors. Medicinal Chemistry, 2012, 8:913-927.
[4].? Nishijima C., Kawamura K., Okamoto N., et al. Regulation of Preimplantation Embryo Development in Mice by FMS-like Tyrosine Kinase 3 Ligand. Journal of Mammalian Ova Research, 2014, 31(1):45-51.
[5].? O'Farrell A.M., Yuen H.A., Smolich B., et al. Effects of SU5416, a small molecule tyrosine kinase receptor inhibitor, on FLT3 expression and phosphorylation in patients with refractory acute myeloid leukemia. Leuk. Res., 2004, 28(7):679-89.
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