title: A novel small molecule agent displays potent anti-myeloma activity by inhibiting the JAK2-STAT3 signaling pathway.
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.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Zubin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Mao
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Du
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Zhejiang, China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Yujia
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Siyu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Ji
authors.affiliation: Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Biyin
authors.initials: B
authors.lastname: Cao
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Kunkun
authors.initials: K
authors.lastname: Han
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Zhejiang, China.
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: School of Public Health, Medical College, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Qiao
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D056742:Cyclin D2 / Q000096:biosynthesis; D050687:E2F1 Transcription Factor / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006835:Hydrazones / Q000627:therapeutic use*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C080336:CCND2 protein, human; D056742:Cyclin D2; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D006835:Hydrazones; D019253:Proto-Oncogene Proteins c-bcl-2; C000613255:SC99 compound; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: JAK2; SC99; STAT3; cyclin D2; multiple myeloma
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9623-8
references.pmid: 22623533
references.citation: J Biol Chem. 2013 Nov 22;288(47):34181-9
references.pmid: 24114842
references.citation: Mol Interv. 2011 Feb;11(1):18-26
references.pmid: 21441118
references.citation: Blood. 2008 Aug 1;112(3):760-9
references.pmid: 18502826
references.citation: Oncotarget. 2015 Jan 1;6(1):185-95
references.pmid: 25474140
references.citation: J Clin Invest. 2008 May;118(5):1750-64
references.pmid: 18431519
references.citation: Cancer Sci. 2015 Jul;106(7):896-901
references.pmid: 25912076
references.citation: Oncogene. 2002 Mar 27;21(13):2000-8
references.pmid: 11960372
references.citation: Br J Haematol. 2001 Sep;114(3):591-9
references.pmid: 11552984
references.citation: Oncogene. 2004 Oct 18;23(48):8017-23
references.pmid: 15489919
references.citation: Blood. 2007 Aug 15;110(4):1330-3
references.pmid: 17496199
references.citation: Immunity. 1999 Jan;10(1):105-15
references.pmid: 10023775
references.citation: J Clin Invest. 2002 May;109(9):1143-8
references.pmid: 11994402
references.citation: Blood. 2004 Apr 15;103(8):3175-84
references.pmid: 15070700
references.citation: Blood. 2007 Dec 1;110(12):4047-54
references.pmid: 17875808
references.citation: Oncogene. 2000 May 15;19(21):2468-73
references.pmid: 10851045
references.citation: Oncogene. 2005 May 12;24(21):3397-408
references.pmid: 15735721
references.citation: Cancer Res. 2005 Feb 1;65(3):939-47
references.pmid: 15705894
references.citation: Cancer Res. 2005 Dec 15;65(24):11345-53
references.pmid: 16357141
references.citation: Cancer Res. 2013 Mar 15;73(6):1922-33
references.pmid: 23322008
references.citation: Blood. 2005 Jul 1;106(1):296-303
references.pmid: 15755896
references.citation: Blood. 2000 Jun 15;95(12 ):3765-70
references.pmid: 10845908
references.citation: Leukemia. 2005 Jun;19(6):936-44
references.pmid: 15912144
references.citation: Blood. 2011 Feb 10;117(6):1986-97
references.pmid: 21135258
references.citation: EMBO J. 1998 Nov 16;17(22):6670-7
references.pmid: 9822610
references.citation: Biochem J. 2005 Dec 1;392(Pt 2):335-44
references.pmid: 16048438
references.citation: Blood. 2008 Dec 15;112(13):5095-102
references.pmid: 18824601
references.citation: Blood. 2003 Jul 1;102(1):344-52
references.pmid: 12637318
references.citation: Mol Pharmacol. 2011 Apr;79(4):672-80
references.pmid: 21220410
references.citation: Toxicol Lett. 2014 Aug 4;228(3):133-9
references.pmid: 24831963
references.citation: J Biol Chem. 2003 Oct 10;278(41):40026-31
references.pmid: 12874294
references.citation: Clin Cancer Res. 2006 Jan 1;12(1):11-9
references.pmid: 16397018
references.citation: Mol Biol Cell. 2001 Oct;12(10):3282-94
references.pmid: 11598209
references.citation: Leukemia. 1999 May;13(5):735-8
references.pmid: 10374878
references.citation: Cancer Cell. 2004 Feb;5(2):191-9
references.pmid: 14998494
references.citation: Oncogene. 2000 May 15;19(21):2474-88
references.pmid: 10851046
references.citation: Science. 1997 Sep 12;277(5332):1630-5
references.pmid: 9287210
references.citation: Int J Cancer. 2012 Nov 15;131(10):2411-9
references.pmid: 22362357
references.citation: Biochim Biophys Acta. 1998 Aug 10;1366(1-2):139-49
references.pmid: 9714780
references.citation: Mol Cell Biochem. 2014 Mar;388(1-2):25-37
references.pmid: 24242046