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.
- 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.
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.