小分子IL-6/STAT3信号通路抑制剂

叶霁青; 岳晓虹; 孙丽萍

doi:10.7536/PC151219

化学进展 ›› 2016, Vol. 28 ›› Issue (7) :1099-1111 DOI: 10.7536/PC151219

综述与评论

扫码查看或转发全文

小分子IL-6/STAT3信号通路抑制剂

叶霁青, 岳晓虹, 孙丽萍*

作者信息 +

Small Molecule Inhibitors of IL-6/STAT3 Signaling

Ye Jiqing, Yue Xiaohong, Sun Liping*

Author information +

文章历史 +

摘要

IL-6是细胞内广泛存在的一种细胞因子，参与细胞内大量的生物应答。研究表明所有IL-6家族的细胞因子均能激活STAT3蛋白，同时，STAT3被认为是介导IL-6功能的主要因子。IL-6与其受体结合，激活JAKs，从而使STAT3磷酸化激活，活化的STAT3二聚化，向细胞核内转移并与其靶基因特定位点结合从而调节基因的转录活性。大量的证据表明细胞中异常活化的STAT3在肿瘤生成与恶性转化中具有重要作用。研究显示STAT3蛋白也是抗肿瘤药物设计的有效靶点。到目前为止，多种药物设计方法，如基于结构的虚拟筛选、高通量筛选、基于片段的药物设计等被用于STAT3抑制剂的筛选以及设计；文献也已经报道了许多具有抗肿瘤活性的STAT3抑制剂。本文主要介绍了近年来小分子IL-6/STAT3信号通路抑制剂，尤其是作用于STAT3蛋白的小分子抑制剂的研究进展。

Abstract

IL-6 is a widespread cytokine which participates in many biological responses. All members of the IL-6 cytokine family are able to activate STAT3, and STAT3 is also recognized as the main mediator of IL-6 functions. IL-6 binding to cell surface receptors results in the activation of the Janus kinases(JAKs) which cause STAT3 phosphorylated. Then activated STAT3 dimerizes translocates to the nucleus and combines with target genes with specific sites, then activats DNA transcriptional activity. Studies show that the abnormally activated STAT3 in cells plays an important role in tumorigenesis and malignant transformation. Meanwhile, STAT3 is a valid target for novel anticancer drug design. So far, many methods, such as structure-based virtual screening, high throughput screening, fragment-based drug design, have been used to screen and design novel STAT3 inhibitors, and thus several classes of small molecule compounds have been identified as STAT3 inhibitors. In this review, we mainly focus on the small molecule IL-6/STAT3 inhibitors especially target STAT3 protein which have been optimized and identified since 2013.

Contents
1 Introduction
2 Small molecule inhibitors of IL-6/STAT3 signaling pathway
2.1 1,4-Naphthoquinones
2.2 Quinolines
2.3 Derivatives of benzo[b]thiophene-1,1-dioxide
2.4 Derivatives of Niclosamide
2.5 Derivatives of salicylic acid
2.6 6-Aminobenzo[d]thiazole-2-thiols
2.7 Tetrahydropyridinepyrazoles
2.8 Flavonoids
2.9 Coumarins
2.10 Metal-containing compounds
2.11 Other small molecule IL-6/STAT3 inhibitors
3 Conclusion

关键词

STAT3 / 信号通路 / 抑制剂 / 抗肿瘤

Key words

STAT3 / signaling pathway / inhibitor / anticancer

引用本文

引用格式 ▾

叶霁青, 岳晓虹, 孙丽萍. 小分子IL-6/STAT3信号通路抑制剂[J]. 化学进展, 2016, 28(7): 1099-1111 DOI:10.7536/PC151219

Ye Jiqing, Yue Xiaohong, Sun Liping. Small Molecule Inhibitors of IL-6/STAT3 Signaling[J]. Progress in Chemistry, 2016, 28(7): 1099-1111 DOI:10.7536/PC151219

登录浏览全文

4963

注册一个新账户忘记密码

参考文献

原文顺序 | 出版日期 | 本文引用

[1] 侯嘉杰(Hou J J),孙倍成(Sun B C). 生物化学与生物物理进展(Progress in Biochemistry and Biophysics), 2014, 41:69.
[2] Waldner M J, Sebastian F, Neurath M F. International Journal of Biological Sciences, 2012, 8:1248.
[3] Kastritis E, Charidimou A, Varkaris A, Dimopoulos M A. Targeted Oncology, 2009, 4:23.
[4] Hodge D R, Hurt E M, Farrar W L. European Journal of Cancer, 2005, 41:2502.
[5] Miklossy G, Hilliard T S, Turkson J. Nature Reviews Drug Discovery, 2013, 12:611.
[6] Akira S, Nishio Y, Inoue M, Wang X J, We S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T. Cell, 1994, 77:63.
[7] Camporeale A, Poli V. Frontiers in Bioscience, 2012, 17:2306.
[8] Ren Z Y, Mao X, Mertens C, Krishnaraj R, Qin J, Mandal P K, Romanowski M J, McMurray J S, Chen X. Biochemical and Biophysical Research Communications, 2008, 374:1
[9] Lim C P, Cao X M. Molecular BioSystems, 2006, 2:536.
[10] Li C, Cao X. Mol. BioSyst., 2006, 2:536.
[11] Parka I H, Li C. J. Mol. Recognit., 2011, 24:254.
[12] Johnston P A, Grandis J R. Mol. Interv., 2011, 11:18.
[13] Aaronson D S, Horvath C M. Science, 2002, 296:1653.
[14] Heinrich P C, Iris B, Serge H, Hermanns, H M, Gerhard M N, Fred S. Biochemical Journal, 2003, 374:1.
[15] Krebs D L, Hilton D J. Journal of Cell Science, 2000, 113:2813.
[16] Shuai K. Oncogene, 2000, 21:2638.
[17] Shuai K, Liu B. Nat. Rev. Immunol., 2005, 5:593.
[18] Yasukawa H, Sasaki A, Yoshimura A. Annu. Rev. Immunol., 2000, 18:143.
[19] Yamada S, Shiono S, Joo A, Yoshimura A. FEBS Lett., 2003, 534:190.
[20] Yu H, Kortylewski M, Pardoll D. Nat. Rev Immunol., 2007, 7:41.
[21] Barbieri I, Pensa S, Pannellini T, Quaglino E, Maritano D, Demaria M, Voster A, Turkson J, Cavallo F, Watson C J, Provero P, Musiani P, Poli V. Cancer Res., 2010, 70:2558.
[22] Wang L, Yi T M. Journal of Experimental Medicine, 2009, 206:1431.
[23] 贾林梓(Jia L Z),冯英明(Feng Y M). 现代肿瘤医学(Journal of Modern Oncology), 2008, 16:2213.
[24] Grivennikov S, Karin E, Terzic J, Mucida D, Yu G Y, Vallabhapurapu S, Scheller J, Stefan R J, Cheroutre H, Eckmann L, Karin M. Cancer Cell, 2009, 15:241.
[25] Zheng T S, Hong X H, Wang J B, Pei T M, Liang Y J, Yin D L, Song R P, Song X, Lu, Shuyi Qi Z Y, Liu J R, Sun B S, Xie C M, Pan S G, Li Y J, Luo X H, Li S, Fang X, Bhatta N, Jiang H C, Liu L X. Hepatology, 2014, 59:935.
[26] He M, Young C Y. Mini-Reviews in Medicinal Chemistry, 2009, 9:395.
[27] Camporeale A, Poli V. Frontiers in Bioscience, 2012, 17:2306.
[28] Debnath B, Xu S, Neamati S. J. Med. Chem., 2012, 55:6645.
[29] Hayashi M, Rho M C, Enomoto A, Fukami A, Kim Y P, Kikuchi Y J, Sunazuka T, Hirose T, Komiyama K, Omura S. Proc. Natl. Acad. Sci. U. S. A., 2002, 99:14728.
[30] Tyner J W, Bumm T G, Deininger J, Wood L, Aichberger K J, Loriaux M M, Druker B J, Burns C B, Fantino E, Deininger M W. Blood, 2010, 115:5232.
[31] Hedvat M, Huszar D, Herrmann A, Herrmann H, Gozgit J M, Schroeder A, Sheehy A, Buettner R, Proia D, Kowolik C M, Xin H, Armstrong B, Bebernitz G, Weng S B, Wang L, Ye M W, McEachern K, Chen H W, Morosini D, Bell K, Alimzhanov M, Ioannidis S, McCoon P, Cao Z A, Yu H, Jove R, Zinda M. Cancer Cell, 2009, 16:487.
[32] Hao Y S, Chapuy B, Monti S, Sun H, Rodig S J, Shipp M A. Blood, 2013, 122:4230.
[33] Huang S B, Sinicrope F A. Molecular Cancer Thrapeutics, 2010, 9:742.
[34] Ferrajoli A, Faderl S, Van Q, Van Q, Koch P, Harris D, Liu Z M, Halevy I H, Wang Y T, Kantarjian H M, Priebe W, Estrov Z. Cancer Research, 2007, 67:11291.
[35] Bharti A C, Donato N, Aggarwal B B. Journal of Immunology, 2003, 171:3863.
[36] Ren X M, Duan L, He Q, Zhang Z, Zhou Y, Wu D H, Pan J X, Pei D Q, Ding K. ACS Med. Chem. Lett., 2010, 1:454.
[37] Song H, Wang R, Wang S, Lin J. Proc. Natl. Acad. Sci. U.S.A., 2005, 102:4700.
[38] Siddiquee K, Zhang S, Guida W C, Blaskovich M A, Greedy B, Lawrence H R, Yip M L, Jove R, McLaughlin M M, Lawrence N J, Sebti S M, Turkson J. Proc. Natl. Acad. Sci. U.S.A., 2007, 104:7391.
[39] Matsuno K J, Masuda Y, Uehara Y, Sato H, Muroya A, Takahashi O, Yokotagawa T, Furuya T, Okawara T, Otsuka M, Ogo N, Ashizawa T, Oshita C, Tai S, Ishii H, Akiyama Y, Asai A. Med. Chem. Lett., 2010, 1:371.
[40] Schust J, Sperl B, Hollis A, Mayer T U, Berg T. Chemistry & biology, 2006, 13:1235.
[41] Yu Z Y, Huang R, Xiao H, Sun W F, Shan Y J, Wang B, Zhao T T, Dong B, Zhao Z H, Liu X L, Wang S Q, Yang R F, Luo Q L, Cong Y W. International Journal of Cancer, 2010, 127:1259.
[42] Hellsten R, Johansson M, Dahlman A, Dizeyi N, Sterner O, Bjartell A. Prostate, 2008, 68:269.
[43] Don-Doncow N, Escobar Z, Johansson M, Kjellström S, Garcia V, Munoz E, Sterner O, Bjartell A, Hellsten R. Journal of Biological Chemistry, 2014, 289:15969.
[44] Bhasin D, Cisek K, Pandharkar T, Regan N, Li C L, Pandit B, Linb J Li P K. Bioorganic & Medicinal Chemistry Letters, 2008, 18:391.
[45] Lin L, Hutzen B, Li P K, Ball S, Zuo M X, Angelis D S, Foust E, Sobo M, Friedman L, Bhasin D, Cen L, Li C L, Lin J Y. Neoplasia, 2010, 12:39.
[46] Yu W Y, Xiao H, Lin J, Li C L. J. Med. Chem., 2013, 56:4402.
[47] Shi Z B, Zhang L, Bin Z Y, Cao X R, Gong Z N, Li J X. Letters in Drug Design & Discovery, 2013, 10:420.
[48] Chen H J, Yang Z D, Ding C Y, Chu L L, Zhang Y S, Terry K, Liu H L, Shen Q, Zhou J. European Journal of Medicinal Chemistry, 2013, 62:498.
[49] Chen H J, Yang Z D, Ding C Y, Chu L L, Zhang Y S, Terry K, Liu H L, Shen Q, Zhou J. ACS Med. Chem. Lett., 2013, 4:180.
[50] Chen H J, Yang Z D, Ding C Y, Xiong A L, Wild C, Wang L L, Ye N, Cai G, Flores M R, Ding Y, Shen Q, Zhou J. European Journal of Medicinal Chemistry, 2014, 82:195.
[51] Fletcher S, Singh J, Zhang X L, Yue P B, Page B D G, Sharmeen S, Shahani V M, Zhao W, Schimmer A D, Turkson J, Gunning P T. ChemBioChem, 2009, 10:1959.
[52] Zhang X L, Yue P, Page B D G, Li T, Zhao W, Namanja A T, Paladino D, Zhao J H, Chen Y, Gunning P T, Turkson J. Proc. Natl. Acad. Sci. U. S. A., 2012, 109:9623.
[53] Page B D G, Croucher D C, Li Z H, Haftchenary S, Jimenez-Zepeda V H, Atkinson J, Spagnuolo P A, Wong Y L, Colaguori R, Lewis A M, Schimmer A D, Trudel S, Gunning P T. J. Med. Chem., 2013, 56:7190.
[54] Haftchenary S, Luchman H A, Jouk A O, Veloso A J, Page B D G, Cheng X R, Dawson S S, Grinshtein N, Shahani V M, Kerman K, Kaplan D R, Griffin C, Aman A M, Al-awar R, Weiss S, Gunning P T. ACS Med. Chem. Lett., 2013, 4:1102.
[55] Urlam M K, Pireddu R, Ge Y Y, Zhang X L, Sun Y, Lawrence H R, Guida W C, Sebti S M, Lawrence N J. Med. Chem. Comm., 2013, 4:932.
[56] Zhang X L, Sun Y, Pireddu R, Yang H, Urlam M K, Lawrence H R, Guida W C, Lawrence N J, Sebti S M. Cancer Res., 2013, 73:1922.
[57] Zhang M M, Zhu W L, Li Y X. European Journal of Medicinal Chemistry, 2013, 62:301.
[58] Ameriks M K, Bembenek S D, Burdett M T, Choong I C, Edwards J P, Gebauer D, Gu Y, Karlsson L, Purkey H E, Staker B L, Sun S Q, Thurmond R L, Zhu J. Bioorganic & Medicinal Chemistry Letters, 2010, 20:4060.
[59] Revanna C. N, Basappa, Srinivasa V, Li F, Siveen K S, Dai X Y, Swamy S N, Bhadregowda D. G, Sethi G, Mantelingu K, Bender A, Rangappa K S. Med. Chem. Commun., 2014, 5:32.
[60] Subash S, Subramanian P. Molecular and Cellular Biochemistry, 2009, 327:153.
[61] Gupta S C, Phromnoi K, Aggarwal B B. Biochemical Pharmacology, 2013, 85:898.
[62] Suematsu N, Hosoda M, Fujimori K. Neuroscience Letters, 2011, 504:223.
[63] Michaud-Levesque J, Bousquet-Gagnon N, Béliveau R. Experimental Cell Research, 2012, 318:925.
[64] Cao H H, Tse A K, Kwan H, Yu H, Cheng C, Su T, Fong W F, Yu Z. Biochemical Pharmacology, 2014, 87:424.
[65] Selvendiran K, Koga H, Ueno T, Yoshida T, Maeyama M, Torimura T, Yano H, Kojiro M, Sata M. Cancer Res., 2006, 66:4826.
[66] Tan J, Luo D. US2011201565-A1, 2011.
[67] Yang M Y, Wang C J, Chen N F, Ho W H, Lu F J, Tseng T H. Chemico-Biological Interactions, 2014, 213:60.
[68] Lee J, Chiang S Y, Nama D, Chung W S, Lee J, Na Y S, Sethi G, Ahn K S. Cancer Letters, 2014, 345:140.
[69] Li S S, Priceman S J, Xin H, Zhang W, Deng J H, Liu Y, Huang J B, Zhu W S, Chen M, Hu W, Deng X M, Zhang J, Yu H, He G Y. PloS One, 2013,8:e81657.
[70] Zhu J F, Li Z J, Zhang G S, Meng K, Kuang W Y, Li J, Zhou X F, Rui juan Li, Peng H L, Dai C W, Shen J K, Gong F J, Xu Y X, Liu S F. PloS One., 2011, 6:e23720.
[71] Xu H T, Zhang S Y. Phytother Research, 2013, 27:1524.
[72] Zhao Y, Yao J, Wu X P, Zhao L, Zhou Y X, Zhang Y, You Q D, Guo Q L, Lu N, Molecular Carcinogenesis, 2014, 54:e81.
[73] Xue P P, Zhao Y, Liu Y, Yuan Q Y, Xiong C M, Ruan J L. Chemico-Biological Interactions, 2014, 209:25.
[74] Kim K J, Kim J Y, Kim H J, Park K G, Harris R A, Cho W J, Lee J T, Lee I K. PloS One, 2013, 8:65.
[75] Kim S M, Lee J H, Sethi G, Kim C, Baek H S, Nam D, Chung W S, Kim S H, Shim B S, Ahn K S. Cancer Letters, 2014, 354:153.
[76] Turkson J, Zhang S, Mora L B, Burns A, Sebti S, Jove R. J. Biol. Chem., 2005, 38:32979.
[77] Turkson J, Zhang S, Palmer J, Kay H, Stanko J, Mora L B, Sebti S, Yu H, Jove R. Mol. Cancer Ther., 2004, 12:1533.
[78] Kim N H, Lee M Y, Park S J, Choi J S, Oh M K, Kim I S. Immunology, 2007, 122:607.
[79] Kim N H, Park H J, Oh M K, Kim I S. BMB Reports, 2013, 46:59.
[80] Sebti S M, Lawrence N J, Turkson J. US20140303134 A1, 2013.
[81] Ma D L, Liu L J, Leung K H, Chen Y T, Zhong H J, Chan D S H, Wang H M D, Leung C H. Angew. Chem., 2014, 126:1.
[82] Huang W, Dong Z, Wang F, Peng H, Liu J Y, Zhang J T. ACS Chemical Biology, 2014, 9(5):1188.
[83] Zhang M M, Zhu W L, Ding N, Zhang W, Li Y G. J. Bioorganic & Medicinal Chemistry Letters, 2013, 23:2225.
[84] Bharadwaj U, Eckols T K, Kolosov M, Kasembeli M M., Adam A, Torres D, Zhang X, Dobrolecki L E, Wei W, Lewis M T, Dave B, Chang J C, Landis M D, Creighton C J, Mancini M A, Tweardy D J. Oncogene, 2014, 34:1.
[85] Liu J W, Zhang Q, Ye Y S, Li W G, Liu J L, Zhan R T, Chen W W, Yu Q. Phytomedicine International Journal of Phytotherapy & Phytopharmacology, 2014, 21:1088.
[86] Shanmugam M K, Rajendran P, Li F, Kim C, Sikka S, Siveen K S, Kumar A P, Ahn K S, Sethi G. Molecular Carcinogenesis, 2015, 54:971.
[87] Xu S, Grande F, Garofalo A, Neamati N. Molecular Cancer Research, 2013, 12:937.
[88] 岳晓虹(Yue X H),叶霁青(Ye J Q),孙丽萍(Sun L P).长三角药物化学研讨会会议论文集(Proceedings of Yangtze River Delta Symposium on Medicinal Chemistry),2014, 105.
[89] 叶霁青(Ye J Q),岳晓虹(Yue X H),张海琪(Zhang H Q),李明涛(Li M T),孙丽萍(Sun L P). 长三角药物化学研讨会论文集(Proceedings of Yangtze River Delta Symposium on Medicinal Chemistry),2015. 41.
[90] 赵璐(Zhao L). 中外医学研究(Chineses and Foreign Medical Research), 2012, 10:144.

PDF (3614KB)

8546

访问

被引

详细

导航

Received	Published	Revised
2015-12-01	2016-07-15	2016-03-01
Online Date
2016-05-17

摘要

Abstract

关键词

Key words

中图分类号

引用本文

参考文献