Tyrosinekinase-IN-1是多靶点的酪氨酸激酶抑制剂，抑制KDR，Flt-1，FGFR1和PDGFRα的IC50值分别为4，20，4，2nM。
Tyrosine kinase-IN-1 is a multi-targeted tyrosine kinase inhibitor with IC50s of 4, 20, 4, 2 nM for KDR, Flt-1, FGFR1 and PDGFRα, respectively.
Tyrosine kinase-IN-1 is from reference (compound 8K)[1].
Tyrosine kinase-IN-1 shows a reasonable PK profile (AUC(0-∞)=1.9, t1/2=4.6 h). It has a favorable oral bioavailability (F=63%) in rats[1].
[1]. Moon K, et al. The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorganic & Medicinal Chemistry Letters 22 (2012) 4979-4985
Kinase experiment: | Kinase Inhibition Assays Kinase activities of KDR and PDGFRα are measured as the percent of ATP consumed following the kinase reaction using luciferaseluciferin-coupled chemiluminescence. Kinase reactions are initiated by combining test compound (Tyrosine kinase-IN-1), ATP, kinases and substrates in a 20 mL volume using 384-well microtiter plates. For KDR, the final reaction mixture contained 3 mM ATP, 1.6 mM poly(Glu, Tyr) 4:1 and 1.5 nM KDR of residues D807-V1356 with an N-terminal GST tag. For PDGFRα, the final reaction mixture contained 2 mM ATP, 10 mM MBP and 14 nM PDGFRα of residues Q551-L1089 with an N-terminal GST tag. The reaction mixture is incubated at room temperature for 4 h (KDR) or 2 h PDGFRα before a 20 mL aliquot of Kinase Glo is added and luminescence signal is measured using a Victor2 plate reader. Total ATP consumption is limited below 50%[1]. |
参考文献: [1]. Moon K, et al. The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorganic & Medicinal Chemistry Letters 22 (2012) 4979–4985 | |
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