Development of a Novel Azaspirane That Targets the Janus Kinase-Signal Transducer and Activator of Transcription (STAT) Pathway in Hepatocellular Carcinoma in Vitro and in Vivo

摘要: Signal transducer and activator of transcription 3 (STAT3) is a factor that regulates genes involved in cell growth, proliferation, survival, given its association with many types cancers, it has recently emerged as promising target for therapy. In this work, we present the synthesis N-substituted azaspirane derivatives their biological evaluation against hepatocellular carcinoma (HCC) cells (IC50 = 7.3 μm), thereby identifying 2-(1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5) undecane (CIMO) potent inhibitor JAK-STAT pathway selectivity over normal LO2 > 100 μm). The lead compound, CIMO, suppresses proliferation HCC achieves effect by reducing both constitutive inducible phosphorylation JAK1, JAK2, STAT3. Interestingly, CIMO displayed inhibition Tyr-705 phosphorylation, which required nuclear translocation STAT3, but no on Ser-727 phosphorylation. accumulates cancer sub-G1 phase decreases STAT3 nucleus causes down-regulation regulated via Suppression knockdown mRNA using siRNA transfection similar viability cells. Furthermore, significantly decreased tumor development an orthotopic mouse model through modulation phospho-STAT3, Ki-67, cleaved caspase-3 tissues. Thus, represents chemically novel biologically vitro vivo validated targets potential treatment.