生物活性

• 靶点

  FLT3 IC50:0.74nM

  Mer IC50:0.8nM

• 描述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 K_is 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. 72h treatment of 300 nM UNC2025 induced apoptosis in NSCLC H2228, A549, Colo699 and H1299 cells. 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%. 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.
• 作用机制UNC2025 inhibited Mer and FLT3 kinase activity in an ATP competitive manner.