A novel small molecule agent displays potent anti-myeloma activity by inhibiting the JAK2-STAT3 signaling pathway
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Zubin Zhang1,*, Hongwu Mao1,*, Xiaolin Du1,*, Jingyu Zhu2, Yujia Xu1, Siyu Wang1, Xin Xu1, Peng Ji4, Yang Yu4, Biyin Cao1, Kunkun Han1, Tingjun Hou2, Zhuan Xu5, Yan Kong5, Gaofeng Jiang6, Xiaowen Tang3, Chunhua Qiao4, Xinliang Mao1,7
1Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
2College of Pharmaceutical Sciences, Zhejiang University, Zhejiang, China
3Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
4Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
5Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China
6School of Public Health, Medical College, Wuhan University of Science and Technology, Wuhan, China
7Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
*These authors have contributed equally to this work
Xinliang Mao, e-mail: Xinliangmao@suda.edu.cn
Keywords: SC99, JAK2, STAT3, cyclin D2, multiple myeloma
Received: June 29, 2015 Accepted: January 17, 2016 Published: January 22, 2016
The oncogenic STAT3 signaling pathway is emerging as a promising target for the treatment of multiple myeloma (MM). In the present study, we identified a novel STAT3 inhibitor SC99 in a target-based high throughput screen. SC99 inhibited JAK2-STAT3 activation but had no effects on other transcription factors such as NF-κB, and kinases such as AKT, ERK, and c-Src that are in association with STAT3 signaling pathway. Furthermore, SC99 downregulated the expression of STAT3-modulated genes, including Bcl-2, Bcl-xL, VEGF, cyclin D2, and E2F-1. By inhibiting the STAT3 signaling, SC99 induced MM cell apoptosis which could be partly abolished by the ectopic expression of STAT3. Furthermore, SC99 displayed potent anti-MM activity in two independent MM xenograft models in nude mice. Oral administration of SC99 led to marked decrease of tumor growth within 10 days at a daily dosage of 30 mg/kg, but did not raise toxic effects. Taken together, this study identified a novel oral JAK2/STAT3 inhibitor that could be developed as an anti-myeloma agent.
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