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Encheng Bai,1,2,* Lehe Yang,1,* Youqun Xiang,2,* Wanle Hu,3 Caleb Li,4 Jiayuh Lin,5 Xuanxuan Dai,2 Guang Liang,1 Rong Jin,2 Chengguang Zhao1 1Chemical Biology Research Center, School of Pharmaceutical Sciences, 2Department of Epidemiology, First Affiliated Hospital, 3Department of Coloproctology, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 4Dublin Coffman High School, Dublin, OH, 5Department of Biochemistry and Molecular Biology, University of Maryland Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA *These authors contributed equally to this work Background: Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. The poor prognosis of this disease highlights the urgent need to develop more effective therapies. Activation of the STAT3 represents a potential drug target for pancreatic cancer therapy. Currently, clinically available small-molecule inhibitors targeting STAT3 are lacking. Methods: Through bioassay screening and molecular docking, we identified a small molecule L61H46 that can potently target constitutive STAT3 signaling and kill human pancreatic cancer cells in vitro and in vivo. Results: L61H46 effectively reduced colony formation and the viability of pancreatic cancer cells in a dose-dependent manner with half-maximal inhibitory concentration (IC50) values in the range between 0.86 and 2.83µM. L61H46 significantly inhibited STAT3 phosphorylation (Tyr705) and the subsequent nucleus translocation but did not downregulate STAT1 phosphorylation. Moreover, L61H46 demonstrated a potent activity in suppressing pancreatic tumor growth in BXPC-3 xenograft model in vivo. Furthermore, L61H46 showed no signs of adverse effects on liver, heart, and kidney cells in vivo. Conclusion: Collectively, our results suggest that L61H46 could be further optimized into a highly potent STAT3 inhibitor for the treatment of pancreatic cancer. Keywords: L61H46, STAT3, cancer therapy, interleukin-6, pancreatic cancer

Hailun Zheng,1,2,* Huang Hong,1,* Lulu Zhang,1,2,* Xiong Cai,1,2 Meng Hu,1,2 Yuepiao Cai,2 Bin Zhou,1 Jiayuh Lin,3 Chengguang Zhao,2 Wanle Hu1 1Department of Coloproctology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 2Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Biochemistry and Molecular Biology, University of Maryland Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MA, USA *These authors contributed equally to this work Abstract: Activation of the signal transducer and activator of transcription 3 (STAT3) is observed in multiple cancer types, including gastric cancer, and represents a potential drug target for chemotherapy. Currently, clinically available small-molecule inhibitors targeting STAT3 are lacking. Here, we report that nifuratel, an antiprotozoal and antifungal drug, is a potent inhibitor of STAT3. We found that nifuratel significantly suppressed proliferation and induced apoptosis of gastric cancer cells. Studies of the mechanism of action of nifuratel indicated that it acts by inhibiting the constitutive and interleukin-6-induced STAT3 activation. Taken together, our findings demonstrate that nifuratel may be a novel, clinically accessible STAT3 inhibitor in gastric cancer cells. Keywords: nifuratel, STAT3, gastric cancer, inhibitor, drug