5,6-Dimethyl-1,3-dihydrobenzo[c][1,2,5]thiadiazole-2,2-dioxide as new STAT3 inhibitor

As part of our ongoing investigations into the development of novel STAT3 inhibitors, through a computational repositioning approach, we identified the 5,6-dimethyl-1,3-dihydrobenzo[c][1,2,5] thiadiazole-2,2- dioxide I (NCI database, Figure 1) as a new candidate targeting the STAT3 SH2 domain. Since it exhibited an interesting inhibitory activity (inh. % = 81.6 at 30 μM), we investigated the molecular basis of its binding mode by synthesizing a set of derivatives showing different substitution patterns (Figure 1). The SAR study on these analogues highlighted several essential features to ensure inhibitory activity against STAT3. Furthermore, spectroscopic and spectrophotometric studies suggested a possible mechanism of interaction for product I. The results of our investigation will be presented.