New STAT3 inhibitors: identification of a lead

STATs (Signal Transducers and Activators of Transcription) are latent cytoplasmic proteins transducing signals through the cytoplasm and acting as transcription factors in the nucleus (1). They are constituted by several structurally and functionally conserved domains and, among them, the Src homology 2 (SH2) domain is essential for STATs activation cascade. In particular, we focused our attention on STAT3 since it has been found constitutively activated in a wide variety of human solid and blood tumors, in consequence to a deregulation of cytokine receptors, growth factors and Janus kinases (JAK) activity (2). Furthermore, the inhibition of persistently activated STAT3 specifically suppresses cancer cell survival and induces tumor regression, but has only little effects in normal cells. For these reasons, STAT3 can be considered as a validated target for anticancer therapy (3). During our ongoing researches, in the attempt to identify new STAT3 inhibitors, we designed and synthesized three series of 1,2,5-oxadiazole derivatives, bearing at position 3 the ureidic, the carboxamidic and the sulfonamidic function, respectively (4). The encouraging STAT3 inhibitory activity exhibited by several of them in the dual luciferase assay, suggested us to evaluate if they were able to directly interact with STAT3, and specifically with the SH2 domain, through the Alpha-Screen based assay. These studies revealed that compound MD77 (N-[4-(4-chlorophenyl)-1,2,5-oxadiazol-3-yl]-4-(trifluoromethyl) benzamide) showed an interesting ability to bind the STAT3-SH2 domain (IC50 = 17.7 uM) in a dose dependent manner. Moreover MD77 anti-proliferative activity was evaluated on a panel of 58 cancer cell lines, confirming its good biological profile (GI50 around 2 µM in most of cell lines). In order to investigate MD77 binding mode, computational studies were performed, supported by crystallographic analysis (5). The obtained results highlight MD77 as a promising candidate for the development of direct STAT3 inhibitors.