关键词： Antitumor Drug repurposing High-throughput screening JAK/STAT3 Zelnorm

Mesh ： Animals Antineoplastic Agents / pharmacology therapeutic use Apoptosis / drug effects Cell Line, Tumor Cell Proliferation / drug effects G1 Phase Cell Cycle Checkpoints / drug effects Humans Indoles / pharmacology therapeutic use Janus Kinases / antagonists & inhibitors metabolism Mice, Nude Neoplasms / drug therapy genetics metabolism Protein Kinase Inhibitors / pharmacology therapeutic use Receptors, Serotonin, 5-HT4 / genetics STAT3 Transcription Factor / antagonists & inhibitors metabolism Serotonin 5-HT4 Receptor Agonists / pharmacology therapeutic use Signal Transduction / drug effects

来  源：   DOI：10.1007/s10637-019-00790-8   PDF(Sci-hub)

Abstract：
The Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays central roles in cancer cell growth and survival. Drug repurposing strategies have provided a valuable approach for developing antitumor drugs. Zelnorm (tegaserod maleate) was originally designed as an agonist of 5-hydroxytryptamine 4 receptor (5-HT4R) and approved by the FDA for treating irritable bowel syndrome with constipation (IBS-C). Through the use of a high-throughput drug screening system, Zelnorm was identified as a JAK/STAT3 signaling inhibitor. Moreover, the inhibition of STAT3 phosphorylation by Zelnorm was independent of its original target 5-HT4R. Zelnorm could cause G1 cell cycle arrest, induce cell apoptosis and inhibit the growth of a variety of cancer cells. The present study identifies Zelnorm as a novel JAK/STAT3 signaling inhibitor and reveals a new clinical application of Zelnorm upon market reintroduction.
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