Hitting the right spot: Mechanism of action of OPB‐31121, a novel and potent inhibitor of the Signal Transducer and Activator of Transcription 3 (STAT3)

• DOI: 10.1016/j.molonc.2015.02.012
• Publication Date: 2015-03-05T04:00:21Z
• Authors: Lara Brambilla; Davide Genini; Erik Laurini; Jessica Merulla; Laurent Perez; Maurizio Fermeglia; Giuseppina M. Car...; Sabrina Pricl; Carlo V. Catapano
• Keywords: Isothermal Titration Calorimetry; Mechanism of Action; Mode of Action

STAT3 is a key element in many oncogenic pathways and, like other transcription factors, an attractive target for development of novel anticancer drugs. However, interfering with functions has been difficult task and very few small molecule inhibitors have made their way to the clinic. OPB‐31121, compound currently clinical trials, reported affect signaling, although its mechanism action not unequivocally demonstrated. In this study, we used combined computational experimental approach investigate molecular mode interaction OPB‐31121 STAT3. parallel, similar studies were performed known (STAT3i) validate our approach. Computational docking dynamics simulation (MDS) showed that interacted high affinity SH2 domain Interestingly, there was no overlap binding site those STAT3i. predictions confirmed by vitro assays competition experiments along site‐directed mutagenesis critical residues domain. Isothermal titration calorimetry demonstrated remarkably Kd (10 nM) 2–3 orders lower than Notably, ranking potency compounds observed terms inhibition phosphorylation, cancer cell proliferation clonogenicity. These results suggest efficacy might be related unique features characteristics make promising candidate further interesting lead designing new, more effective