STAT3 is a key element inmany oncogenic pathways and, like other transcriptionfactors, is an attractive target for development of novel anticancer drugs. However, interfering with STAT3 functions has been a difficult task and very fewsmallmolecule inhibitors havemade theirway to the clinic. OPB-31121, an anticancer compound currently in clinical trials, has been reported to affect STAT3 signaling, although its mechanism of action has not been unequivocally demonstrated. In this study, we used a combined computational and experimental approach to investigate the molecular target and the mode of interaction of OPB-31121 with STAT3. In parallel, similar studies were performed with known STAT3 inhibitors (STAT3i) to validate our approach. Computational docking and molecular dynamics simulation (MDS) showed that OPB-31121 interacted with high affinity with the SH2 domain of STAT3. Interestingly, there was no overlap of the OPB-31121 binding site with those of the other STAT3i. Computational predictions were confirmed by in vitro binding assays and competition experiments alongwith site-directedmutagenesis of critical residues in the STAT3 SH2 domain. Isothermal titration calorimetry experiments demonstrated the remarkably high affinity ofOPB-31121 for STAT3 with Kd (10 nM) 2e3 orders lower than other STAT3i. Notably, a similar ranking of the potency of the compoundswas observed in terms of inhibition of STAT3phosphorylation, cancer cell proliferation and clonogenicity. These results suggest that the highaffinity and efficacy of OPB-31121 might be related to the unique features and mode of interaction of OPB-31121 with STAT3. These unique characteristics make OPB-31121 a promising candidate for further development and an interesting lead for designing new,more effective STAT3i.

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)

LAURINI, ERIK;FERMEGLIA, MAURIZIO;PRICL, SABRINA;
2015

Abstract

STAT3 is a key element inmany oncogenic pathways and, like other transcriptionfactors, is an attractive target for development of novel anticancer drugs. However, interfering with STAT3 functions has been a difficult task and very fewsmallmolecule inhibitors havemade theirway to the clinic. OPB-31121, an anticancer compound currently in clinical trials, has been reported to affect STAT3 signaling, although its mechanism of action has not been unequivocally demonstrated. In this study, we used a combined computational and experimental approach to investigate the molecular target and the mode of interaction of OPB-31121 with STAT3. In parallel, similar studies were performed with known STAT3 inhibitors (STAT3i) to validate our approach. Computational docking and molecular dynamics simulation (MDS) showed that OPB-31121 interacted with high affinity with the SH2 domain of STAT3. Interestingly, there was no overlap of the OPB-31121 binding site with those of the other STAT3i. Computational predictions were confirmed by in vitro binding assays and competition experiments alongwith site-directedmutagenesis of critical residues in the STAT3 SH2 domain. Isothermal titration calorimetry experiments demonstrated the remarkably high affinity ofOPB-31121 for STAT3 with Kd (10 nM) 2e3 orders lower than other STAT3i. Notably, a similar ranking of the potency of the compoundswas observed in terms of inhibition of STAT3phosphorylation, cancer cell proliferation and clonogenicity. These results suggest that the highaffinity and efficacy of OPB-31121 might be related to the unique features and mode of interaction of OPB-31121 with STAT3. These unique characteristics make OPB-31121 a promising candidate for further development and an interesting lead for designing new,more effective STAT3i.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11368/2838071
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