A novel small molecule agent displays potent anti-myeloma activity by inhibiting the JAK2-STAT3 signaling pathway

// Zubin Zhang 1, * , Hongwu Mao 1, * , Xiaolin Du 1, * , Jingyu Zhu 2 , Yujia Xu 1 , Siyu Wang 1 , Xin Xu 1 , Peng Ji 4 , Yang Yu 4 , Biyin Cao 1 , Kunkun Han 1 , Tingjun Hou 2 , Zhuan Xu 5 , Yan Kong 5 , Gaofeng Jiang 6 , Xiaowen Tang 3 , Chunhua Qiao 4 , Xinliang Mao 1, 7 1 Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China 2 College of Pharmaceutical Sciences, Zhejiang University, Zhejiang, China 3 Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China 4 Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, China 5 Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China 6 School of Public Health, Medical College, Wuhan University of Science and Technology, Wuhan, China 7 Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China * These authors have contributed equally to this work Correspondence to: 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 ABSTRACT 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.