Mer, Tyro and Axl are members of the TAM subfamily of receptor tyrosine kinases (RTK). FLT3 belongs to type Ⅲ RTKs. Containing an extracellular domain for ligand binding and intracellular kinase domains that mediate autophosphorylation, recruitment of downstream signaling molecules, and signal transduction, RTKs are mediators of cellular proliferation.
UNC2025 is a Mer and FLT3 dual inhibitor. The inhibitory IC50s of UNC2025 against Mer and FLT3 kinase were 0.8 nM and 0.74 nM, respectively, and the Kis were 0.16 nM and 0.59 nM, respectively. In B-ALL 697 cells, UNC2025 inhibited Mer phosphorylation with an IC50 of 2.7 nM and in Molm-14 cells, UNC2025 decreased FLT3 phosphorylation with an IC50 of 14 nM. UNC2025 dose-dependently inhibited colony formation of A549 cells at the concentrations of 50, 100, and 300 nM, and that of Molm-14 cells at the concentrations of 10, 25, and 50 nM[3]. 72h treatment of 300 nM UNC2025 induced apoptosis in NSCLC H2228, A549, Colo699 and H1299 cells[4].
In NSG mice transplanted with B-ALL cells by i.v. injection, a single dose of UNC2025 (3 mg/kg) administrated orally was sufficient to decrease Merphospho-protein levels in bone marrow leukemia cells by greater than 90%[3]. In H2228 or A549 xenografts established in nude mice, UNC2025 administrated at the dose of 50 mg/kg twice daily by oral gavage reduced tumor volume by 70.2% and 61.9%, respectively[4].
作用机制
UNC2025 inhibited Mer and FLT3 kinase activity in an ATP competitive manner.
UNC2025 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
32D cells
Function assay
1 h
Inhibition of EGFR extracellular/transmembrane domain-tagged Mer intracellular domain (unknown origin) expressed in 32D cells assessed as inhibition EGF-stimulated of phosphorylation pretreated for 1 hr prior to EGF stimulation by Western blot analysis, IC50=2.7 nM
25068800
697 cells
Function assay
1 h
Inhibition of Mer phosphorylation in human 697 cells preincubated for 1 hr by densitometry, IC50=2.7 nM
25068800
A549 cells
50-300 nM
Function assay
Inhibition of Mer-mediated colony formation in human A549 cells at 50 to 300 nM measured after 2 weeks by soft agar colony formation assay
25068800
Molm-14 cells
Function assay
1 h
Inhibition of Flt3 phosphorylation in human Molm-14 cells preincubated for 1 hr by densitometry, IC50=0.014 μM
Inhibition of EGFR extracellular/transmembrane domain-tagged Mer intracellular domain (unknown origin) expressed in 32D cells assessed as inhibition EGF-stimulated of phosphorylation pretreated for 1 hr prior to EGF stimulation by Western blot analysis, IC50=2.7 nM
25068800
697 cells
Function assay
1 h
Inhibition of Mer phosphorylation in human 697 cells preincubated for 1 hr by densitometry, IC50=2.7 nM
25068800
A549 cells
50-300 nM
Function assay
Inhibition of Mer-mediated colony formation in human A549 cells at 50 to 300 nM measured after 2 weeks by soft agar colony formation assay
25068800
Molm-14 cells
Function assay
1 h
Inhibition of Flt3 phosphorylation in human Molm-14 cells preincubated for 1 hr by densitometry, IC50=0.014 μM
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