Benzothiadiazole derivatives endowed with STAT3 inhibition

BENZOTHIADIAZOLE DERIVATIVES ENDOWED WITH STAT3 INHIBITION Arianna Gelain (1), Matteo Mori (1), Ettore Gilardoni (1), Luca Regazzoni (1), Alessandro Pedretti (1), Diego Colombo (2), Gary Parkinson (3), Akira Asai (4), Fiorella Meneghetti (1), Stefania Villa (1) 1) Department of Pharmaceutical Sciences, University of Milan, via L. Mangiagalli 25, 20133 Milan, Italy 2) Department of Medical Biotechnology and Translational Medicine, University of Milan, via C. Saldini 50, 20133 Milan, Italy 3) Department of Pharmaceutical and Biological Chemistry – UCL School of Pharmacy, University College London, 29/39 Brunswick Square, WC1N 1AX London, United Kingdom 4) Center for Drug Discovery – Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, 422-8526 Shizuoka, Japan Signal Transducer and Activator of Transcription 3 (STAT3) is a latent cytoplasmic protein over-expressed in various cancer cell lines1,2. As a part of our ongoing research focused on compounds showing STAT3 SH2 domain inhibiting activity3,4, by a virtual screening approach, we identified 5,6-dimethyl-1H,3H -2,1,3-benzothiadiazole-2,2-dioxide (1) as potential inhibitor. Several derivatives were synthesized (Figure 1) and tested. Since compound 1 exhibited the most interesting activity (IC50 = 15.8 ± 0.6 μM by AlphaScreen-based assay), we decided to investigate the mechanism of its activity by liquid chromatography, MS and UV studies, discovering compound 1 unexpected interaction also with cysteine residues5. Figure 1 . Benzothiadiazole-2,2-dioxide derivatives set References 1) Darnell, J. Jr Science, 1997, 277, 1630-1635 2) Turkson, J. and Jove R. Oncogene, 2000, 19, 6613-6626 3) Meneghetti, F.; Villa, S.; Masciocchi, D.; Barlocco, D.; Toma, L.; Han, D.C.; Kwon, B.M.; Ogo, N.; Asai, A.; Legnani, L.; Gelain, A. European J. Org. Chem. 2015, 2015, 4907–4912 4) Porta, F.; Facchetti, G.; Ferri, N.; Gelain, A.; Meneghetti, F.; Villa, S.; Barlocco, D.; Masciocchi, D.; Asai, A.; Miyoshi, N.; Marchianò, S.; Kwon, B.M.; Jin, Y.; Gandin, V.; Marzano, C.; Rimoldi, Eur. J. Med. Chem. 2017, 131, 196–206 5) Mori, M.; Gilardoni, E.; Regazzoni, L.; Pedretti, A.; Colombo, D.; Parkinson, G.; Asai, A,; Meneghetti, F.; Villa, S.; Gelain, A., Molecules 2020, 25(15), 3509.