Identification of a novel STAT3 inhibitor structurally related to the oxadiazole derivative MD77

Signal Transducer and Activator of Transcription 3 (STAT3) is a latent cytoplasmic protein over- expressed in various cancer cell lines.(1,2) STAT3 participates in oncogenesis by stimulating cell proliferation and preventing apoptosis; it has been proven as a suitable and selective(3,4) target for anticancer therapy. With the aim to discover new STAT3 inhibitors,(5-7) we focused our efforts on a compound previously synthesized by our research group, MD77 [4-(4-chloro-phenyl)-1,2,5-oxadiazol-3-N-(4-trifluoromethyl-phenyl)-amide],(8) which had been shown to be able to bind the STAT3 SH2 domain. To improve MD77 activity and selectivity, SAR studies were performed, which allowed us to identify , compound 1 as novel STAT3 direct inhibitor, provided with a better profile with respect to the lead. The synthesis, crystallographic studies, and biological activity of compound 1 will be presented.