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

Zubin Zhang,Yujia Xu,Jingyu Zhu,Zhuan Xu,Chunhua Qiao,Hongwu Mao,Siyu Wang,Xiaowen Tang,Kunkun Han,Xinliang Mao,Xin Xu,Peng Ji,Biyin Cao,Yang Yu,Gaofeng Jiang,Xiaolin Du,Yan Kong,Tingjun Hou

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.

Highlights

Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor widely expressed in many tissues and plays an important role in regulating cellular activities
To find out small molecule compounds that inhibit STAT3 activation and Cyclin D2 (CCND2) transactivation, a luciferase reporter system driven by the CCND2 promoter containing a STAT3 response element was stably established in NIH3T3 cells and was applied to screen a Maybridge chemical library composed of 56000 compounds with unknown functions as described previously [21], from which SC99 was identified
JP31 inhibited STAT3 activation but less potent than SC99 which was probably due to the 3-chloro-4-fluorophenyl group, especially the chlorine and fluorine atoms that were missing from JP31

Summary

Introduction

Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor widely expressed in many tissues and plays an important role in regulating cellular activities. Being activated by a panel of stimuli, including cytokines, such as interleukin-6 (IL-6) [1, 2], and growth factors, such as insulin-like growth factor 1 (IGF-1) [1, 2], STAT3 forms homo- or hetero-dimers before being translocated to the nuclei where it binds to DNA and regulates gene transcription [1, 3]. STAT3 has a broad spectrum of substrate genes including anti-apoptotic Mcl-1, Bcl-2, survivin [4,5,6], and cell cycle regulators (such as D-cyclins, E2F-1). STAT3 is overexpressed in a broad range of cancers including hematological malignancies, including leukemia [10], lymphoma [11] and multiple myeloma (MM) [12, 13]. A recent clinical trial with a STAT3 inhibitor OPB-51602 has been reported for the treatment of MM and acute myeloid leukemia [16]

Methods

Results

Conclusion