Unravelling the interactions between an antiproliferative 1,2,5-oxadiazole derivative and STAT3

In our effort to develop novel direct STAT3 inhibitors, we identified the 1,2,5-oxadiazole I (Figure 1), which showed a promising inhibitory effect on the SH2 domain of STAT3 (inh % = 78.2 at 30 μM, IC50 = 8.2 μM) and a significant antiproliferative activity in the LLC murine model (tumor growth inh % = 82.6 at 75 mg/kg as i.p. daily dose). Since compound I is characterized by a pH-dependent enolization ratio, we decided to investigate whether the interactions with STAT3 could be related to its enolic form. Therefore, we designed several new derivatives (Figure 1) to shed light on this matter: for instance, we synthesized analogues lacking the NH2 group or directly bearing an OH in substitution of the CO function. The results of the inhibition studies performed on these derivatives will be presented.