STAT3 direct inhibitors: from MD77 to AC33

STAT3 (Signal Transducer and Activator of Transcription 3) is a latent cytosolic protein overexpressed in various cancer cell lines which was found to participate in oncogenesis by stimulating cell proliferation and preventing apoptosis [1]. Furthermore, previous studies have shown that blocking constitutively activated STAT3 signaling leads to tumor cell apoptosis, with minimal effect on normal cells [2,3]. This work aims at the synthesis, the structural analysis and the biological evaluation of novel potential antitumor agents, able to inhibit STAT3 protein-protein interaction, starting from MD77 previously identified by our research group [4,5]. Among them, AC33 was selected for further investigations since the AlphaScreen-based assay highlighted its ability to disrupt the STAT3 dimerization, with high selectivity over STAT1 and Grb2. These data induced us to modulate its pharmacokinetic and pharmacodynamic properties. The interesting results obtained will be presented. This work was supported by a PRIN2010 Grant from MIUR, Italy. References: [1] H. Yu, R. Jove, Nat Rev Cancer, 2004, 4, 97-105. [2] R. Buettner, L.B. Mora, R. Jove, Clin Cancer Res, 2002, 8(4), 945-954. [3] T. Bowman, R. Garcia, J. Turkson, R. Jove, Oncogene, 2000, 19, 2474-2488. [4] D-S. Shin, D. Masciocchi, A. Gelain, S. Villa, D. Barlocco, F. Meneghetti, A. Pedretti, Y-M Han, D. C. Han, B.M. Kwon, L. Legnani, L. Toma, Med. Chem. Comm., 2010, 1, 156-164. [5] D. Masciocchi, S. Villa, F. Meneghetti, A. Pedretti, D. Barlocco, L. Legnani, L. Toma, B. M. Kwon, S. Nakano, A. Asai, A. Gelain, Med. Chem. Comm., 2012, 3, 592-599.