The study on 3- phenoxy-1,2,4-oxadiazole derivatives as novel inhibitors for the STAT3 pathways.

Abstract

STAT3 often found constitutively activated in various human cancer. It is well established that persistently activated STAT3 promotes its downstream genes involved in cell proliferation, survival and growth leading to oncogenic transformation. Inhibiting the constitutively activated STAT3, therefore, is a potential anti cancer drug target. 3-phenoxy-1,2,4-oxadiazole (#17690) was found in chemical library , possesses SH2 binding domain homologue with STAT3. SH2 dimerization domain is crucial since only activated STAT3 dimer can translocate into nucleus and induce transcription of corresponding gene. Therefore SH2 domain blocker can be a powerful STAT3 inhibitor. The two newly synthesized derivatives, 3-{(2, 4-dichlorophenoxy) methyl}-5-(trichloromethyl)-1,2,4-oxadiazole (#10117), 3-{(2,4-dichlorophenoxy)methyl}-5-propoxy-1,2,4-oxadiazole (#10181) were synthesized from the lead molecule, #17690 and examined for STAT3 inhibition effect, which ultimately result in tumour suppression. Upon the treatment of the compounds, both of the tyrosine705 and serine 727 phosphorylation were suppressed in glioblastoma cell line, U87-MG and breast adenocarinoma cell line, MDA-MB231, which then leads to the inhibition of proliferation, migration and invasion as well as in the induction of apoptosis. Equivalently related genes such as anti apoptotic BCL-XL, migration and invasion responsible TWIST, pro/active MMP2 and cell proliferation regulating NAIP and c-Myc are suppressed. Also Caspase 3 and PARP , apoptosis inducing genes were upregulated. Conclusively, the two derivatives exhibited anti-tumour growth effect through STAT3 inhibition and the suppression of responsible downstream genes as well as upregulating anti-tumourigenic genes. When tumour were implanted to BALB/c nude mice, upon the intratumoural injection of the two derivatives, #10117 and #10181 exhibited similar tendency. In summary, newly synthesized derivatives of 3-phenoxy-1,2,4-oxadiazole, #10117 and #10181 effectively inhibited STAT3 through the shielding effect of SH2 dimerization site. Accordingly STAT3 responsible downstream tumorigenic genes were suppressed to regress tumorigenesis in mural physiological condition. Altogether, the study suggest that the novel SH2 dimerization domain blockers, 3-{(2, 4-dichlorophenoxy)methyl}-5-(trichloromethyl)-1,2,4-oxadiazole (#10117), 3-{(2,4-dichlorophenoxy)methyl}-5-propoxy-1,2,4-oxadiazole (#10181) is a potent cancer therapeutic agent through impediment of STAT3 signaling pathway.