生物活性

• 描述Receptor tyrosine kinases (RTK) are mediators of cellular proliferation. These transmembrane RTKs contain an extracellular domain for ligand binding and intracellular kinase domains that mediate autophosphorylation, recruitment of downstream signaling molecules, and signal transduction. Type III RTKs, such as PDGFR (platelet-derived growth factor receptor), FGFR (fibroblast growth factor receptor), VEGFR (vascular endothelial growth factor receptor), FLT3 and c-KIT are often overexpressed in tumor and implicated in tumor growth and progression. Tandutinib is an inhibitor of FLT3, PDGFR and c-Kit. The kinase inhibitory IC₅₀s were 0.22, 0.20 and 0.17 μM, respectively. Tandutinib inhibited phosphorylation of WT FLT3 and FLT3-ITD (internal tandem duplication) in Ba/F3 cells with IC₅₀s of 30-100nM. Tandutinib inhibited cell proliferation of the FLT3-ITD-positive cells (Molm-13 and Molm-14 cells） with an IC₅₀ value of 10 nM, whereas the FLT3-ITD-negative cells (THP-1, KG-1, and RS4 cells) were resistant, requiring 1000-fold higher concentrations to inhibit cell growth. Treatment of Molm-14 cells with 1 μM tandutinib resulted in an increase of the percentage of apoptotic cells from a background level of 5% to 51% at 24h and 78% at 96h. Tandutinib preferentially inhibited the growth of blast colonies derived from FLT3 ITD-positive patients with IC₅₀s between 75 and 400 nM. In a nude mice model established by injection of FLT3-ITD-transformed Ba/F3 cells, oral administration of tandutinib at 60 mg/kg bid significantly increased the survival of mice and resulted in a significant reduction in mortality in a mouse bone marrow transplantation model.
• 作用机制Tandutinib inhibits FLT3, PDGFR and c-Kit in an ATP competitive manner.