2. Academic Validation
  3. A novel small molecule agent displays potent anti-myeloma activity by inhibiting the JAK2-STAT3 signaling pathway

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

  • Oncotarget. 2016 Feb 23;7(8):9296-308. doi: 10.18632/oncotarget.6974.
Zubin Zhang 1,  Hongwu Mao 1,  Xiaolin Du 1,  Jingyu Zhu 2,  Yujia Xu 1,  Siyu Wang 1,  Xin Xu 1,  Peng Ji 3,  Yang Yu 3,  Biyin Cao 1,  Kunkun Han 1,  Tingjun Hou 2,  Zhuan Xu 4,  Yan Kong 4,  Gaofeng Jiang 5,  Xiaowen Tang 6,  Chunhua Qiao 3,  Xinliang Mao 1 7
Affiliations

Affiliations

  • 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 Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
  • 4 Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 5 School of Public Health, Medical College, Wuhan University of Science and Technology, Wuhan, China.
  • 6 Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 7 Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
PMID: 26814430 DOI: 10.18632/oncotarget.6974
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.

Keywords

JAK2; SC99; STAT3; cyclin D2; multiple myeloma.

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