Abstract
Pancreatic cancer is lethal in over 90% of cases since it is resistant to current therapeutic strategies. The key role of STAT3 in promoting pancreatic cancer progression has been proven, but effective interventions that suppress STAT3 activities are limited. The development of novel anticancer agents that directly target STAT3 may have potential clinical benefits for pancreatic cancer treatment. Here, we report a new small-molecule inhibitor (N4) with potent antitumor bioactivity, which inhibits multiple oncogenic processes in pancreatic cancer. N4 blocked STAT3 and phospho-tyrosine (pTyr) peptide interactions in fluorescence polarization (FP) assay, specifically abolished phosphor-STAT3 (Tyr705), and suppressed expression of STAT3 downstream genes. The mechanism involved the direct binding of N4 to the STAT3 SH2 domain, thereby, the STAT3 dimerization, STAT3-EGFR, and STAT3-NF-κB cross-talk were efficiently inhibited. In animal models of pancreatic cancer, N4 was well tolerated, suppressed tumor growth and metastasis, and significantly prolonged survival of tumor-bearing mice. Our results offer a preclinical proof of concept for N4 as a candidate therapeutic compound for pancreatic cancer.
Highlights
These authors contributed : Huang Chen, Aiwu Bian
The use of fluorescence polarization (FP) assay for Signal transducer and activator of transcription 3 (STAT3)-Src Homology 2 domain (SH2) drug screening has been previously reported [26]
In the FP assay model, the fluorescence signal was suppressed by all these inhibitors in a concentration-dependent manner, with an IC50 that was consistent with previous reports (Supplementary Fig. S1)
Summary
Phosphorylation of Tyr705 results in homo- or heterodimerization of STAT3, enabling nuclear localization and DNA binding. This triggers downstream gene transcription, which regulates fundamental cellular processes. Indirect inhibitors target the upstream components of the STAT3 pathway that affect STAT3 protein by decreasing its Tyr705 phosphorylation In this group, JAK and SRC kinase are the major drug development targets, and many JAK inhibitors have been evaluated in clinical trials for indications, such as oncology and inflammatory syndromes, and ruxolitinib and tofacitinib have been approved by the United States Food and Drug Administration. STAT3 inhibitors, such as the small-molecule inhibitor BBI-608 and monoclonal antibody SBT-100 have obtained orphan drug identification in pancreatic cancer and are undergoing clinical phase ΙΙΙ and Ι study, respectively. Our data establish N4 as a STAT3 inhibitor that has potential therapeutic value for pancreatic cancer
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