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L61H46 shows potent efficacy against human pancreatic cancer through inhibiting STAT3 pathway

Authors Bai E, Yang L, Xiang Y, Hu W, Li C, Lin J, Dai X, Liang G, Jin R, Zhao C

Received 6 December 2017

Accepted for publication 25 January 2018

Published 23 March 2018 Volume 2018:10 Pages 565—581

DOI https://doi.org/10.2147/CMAR.S159090

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Leylah Drusbosky


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 2.83 µM. 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
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