Biological and computational evaluation of an oxadiazole derivative (MD77) as a new lead for direct STAT3 inhibitors

Signal Transducer and Activator of Transcription 3 (STAT3) is a latent cytoplasmic protein overexpressed in various cancer cell lines. STAT3 participates in oncogenesis by stimulating cell proliferation and preventing apoptosis and it has been proven as a suitable target for anticancer therapy. In order to identify direct STAT3 inhibitors, we performed a binding assay on several previously synthesized 1,2,5-oxadiazole derivatives. Among them, compound MD77, N-[4-(4-chlorophenyl)-1,2,5-oxadiazol-3-yl]-4-(trifluoromethyl) benzamide, showed a good ability to bind the STAT3-SH2 domain in a dose-dependent manner (IC50 = 17.7 μM). Computational studies were carried out to investigate its binding mode. Moreover, compound MD77 showed a significant anti-proliferative activity versus several tumor cell lines. On these bases, compound MD77 was selected as a lead for the future development of direct STAT3 inhibitors.