Signal transducers and activators of transcription 3 (STAT3), a member of the Janus kinase (JAK)/STAT signaling pathway, is a central transcription factor that is activated by phosphorylation of a conserved tyrosine residue (Tyr705) in response to extracellular cytokines and growth factors and is an attractive target for anticancer drug discovery[2]. InS3-54-A18 (STAT3 Inhibitor XX), analog of inS3-54, is a potential lead inhibitor of STAT3, which suppresses STAT3-dependent luciferase expression in dose- and time-dependent manners with IC50 of 8.8-12.6 μM[3]. Wound healing was reduced to 64% and 76% by 5 μM inS3-54-A1 and invasion was reduced to 35% and 13% by 10 μM inS3-54-A1 for A549 and MDA-MB-231 cells, respectively. The expression of STAT3 downstream target genes cyclin D1, survivin, matrix metalloproteinase-9 and vascular endothelial growth factor (VEGF) was decreased in both cell lines following inS3-54-A18 treatment[3]. Oral treatment of inS3-54-A18 (200 mg/kg) significantly reduced tumor growth in a mouse xenograft model of A549 cells compared with the vehicle control treatment, but had no significant effect on mouse body weight[3].
作用机制
InS3-54-A18 acts as STAT3 inhibitor via targeting the DNA-binding domain of STAT3.
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