The Emerging Role of Janus Kinase Inhibitors in the Treatment of Cancer

doi:10.2174/1568009622666220301105214
摘要

癌症是世界范围内的主要死亡原因。 Janus 激酶 (JAK) 信号转导和转录激活子 (STAT) 信号通路被异常激活，从而促进癌变。几种细胞因子是重要的癌症驱动因素。这些蛋白质与受体结合并使用 Janus 激酶 (JAK) 和 STAT 通路来传达它们的反应。癌症风险与 JAK-STAT 系统中的遗传差异有关。在涉及实体瘤细胞系模型的临床前研究中，JAK 抑制剂已被证明可减少 STAT 起始、组织增殖和细胞存在。 JAK 抑制剂，尤其是鲁索替尼、JAK1 或 2 阻滞剂，使细胞系和小鼠模型更容易受到放射疗法、生物反应调节剂疗法和溶瘤病毒治疗的影响。许多 JAK 拮抗剂已经或现在正在癌症患者中作为单一疗法或在临床研究中与其他药物联合进行评估。在临床前研究中，某些 JAK 抑制剂显示出有希望的抗癌作用；然而，明确评估其针对 JAK/STAT 系统在实体瘤中的有效性的临床试验尚未完成。 JAK 抑制是一种针对实体瘤中 JAK/STAT 系统的有前景的策略，值得在临床研究中进一步测试。本文总结了 STATs 的上游加速器 Janus 激酶 (JAKs) 作为一种在各种恶性情况下降低 STAT 活性的技术的作用，这将有助于科学家在未来产生更具体的药物分子。
关键词: 癌症，JAK-STAT 通路，JAK 抑制剂，STAT 过度激活，临床试验，细胞因子。
« Previous Next »
图形摘要

[1] 
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer,  2015, 136(5), E359-E386.
[http://dx.doi.org/10.1002/ijc.29210] [PMID:  25220842] 
[2] 
Karati, D.; Mahadik, K.R.; Trivedi, P.; Kumar, D. Alkylating agents, the road less traversed, changing anticancer therapy. Anticancer. Agents Med. Chem.,  2021, 21, 1-7.
[http://dx.doi.org/10.2174/1871520621666210811105344] [PMID:  34382529] 
[3] 
Godman, C.A.; Joshi, R.; Tierney, B.R.; Greenspan, E.; Rasmussen, T.P.; Wang, H.W.; Shin, D.G.; Rosenberg, D.W.; Giardina, C. HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signaling. Cancer Biol. Ther.,  2008, 7(10), 1570-1580.
[http://dx.doi.org/10.4161/cbt.7.10.6561] [PMID:  18769117] 
[4] 
Shao, Y.; Gao, Z.; Marks, P.A.; Jiang, X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc. Natl. Acad. Sci. USA,  2004, 101(52), 18030-18035.
[http://dx.doi.org/10.1073/pnas.0408345102] [PMID:  15596714] 
[5] 
Shanshan, W.; Hongying, M.; Jingjing, F.; Yiming, Y.; Yu, R.; Rui, Y. CircDTL functions as an oncogene and regulates both apoptosis and ferroptosis in non-small cell lung cancer cells. Front. Genet.,  2021, 12, 743505.
[http://dx.doi.org/10.3389/fgene.2021.743505] [PMID:  34621297] 
[6] 
Yu, Y.; Mao, L.; Cheng, Z.; Zhu, X.; Cui, J.; Fu, X.; Cheng, J.; Zhou, Y.; Qiu, A.; Dong, Y.; Zhuang, X.; Lu, Y.; Lian, Y.; Tian, T.; Wu, S.; Chu, M. A novel regQTL-SNP and the risk of lung cancer: A multi-dimensional study. Arch. Toxicol.,  2021, 95(12), 3815-3827.
[http://dx.doi.org/10.1007/s00204-021-03170-5] [PMID:  34596730] 
[7] 
Zhang, C.; Li, N.; Liu, Y.Y.; Yuan, T.; Yang, S.; Wang, X.P. Cox15 is a novel oncogene that required for lung cancer cell proliferation. Biochem. Biophys. Res. Commun.,  2021, 578, 70-76.
[http://dx.doi.org/10.1016/j.bbrc.2021.09.010] [PMID:  34547626] 
[8] 
Borish, L.C.; Steinke, J.W. Cytokines and chemokines. J. Allergy Clin. Immunol.,  2003, 111(2)(Suppl.), S460-S475.
[http://dx.doi.org/10.1067/mai.2003.108] [PMID:  12592293] 
[9] 
Brennan, F.M.; McInnes, I.B. Evidence that cytokines play a role in rheumatoid arthritis. J. Clin. Invest.,  2008, 118(11), 3537-3545.
[http://dx.doi.org/10.1172/JCI36389] [PMID:  18982160] 
[10] 
Hosseini, A.; Gharibi, T.; Marofi, F.; Javadian, M.; Babaloo, Z.; Baradaran, B. Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases. J. Cell. Physiol.,  2020, 235(9), 5903-5924.
[http://dx.doi.org/10.1002/jcp.29593] [PMID:  32072644] 
[11] 
Pesu, M.; Laurence, A.; Kishore, N.; Zwillich, S.H.; Chan, G.; O’Shea, J.J. Therapeutic targeting of Janus kinases. Immunol. Rev.,  2008, 223, 132-142.
[http://dx.doi.org/10.1111/j.1600-065X.2008.00644.x] [PMID:  18613833] 
[12] 
Vainchenker, W.; Dusa, A.; Constantinescu, S.N. JAKs in pathology: Role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin. Cell Dev. Biol.,  2008, 19(4), 385-393.
[http://dx.doi.org/10.1016/j.semcdb.2008.07.002] [PMID:  18682296] 
[13] 
Ungureanu, D.; Wu, J.; Pekkala, T.; Niranjan, Y.; Young, C.; Jensen, O.N.; Xu, C.F.; Neubert, T.A.; Skoda, R.C.; Hubbard, S.R.; Silvennoinen, O. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat. Struct. Mol. Biol.,  2011, 18(9), 971-976.
[http://dx.doi.org/10.1038/nsmb.2099] [PMID:  21841788] 
[14] 
Sanz, A.; Ungureanu, D.; Pekkala, T.; Ruijtenbeek, R.; Touw, I.P.; Hilhorst, R.; Silvennoinen, O. Analysis of Jak2 catalytic function by peptide microarrays: The role of the JH2 domain and V617F mutation. PLoS One,  2011, 6(4), e18522.
[http://dx.doi.org/10.1371/journal.pone.0018522] [PMID:  21533163] 
[15] 
Dawson, M.A.; Bannister, A.J.; Göttgens, B.; Foster, S.D.; Bartke, T.; Green, A.R.; Kouzarides, T. JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature,  2009, 461(7265), 819-822.
[http://dx.doi.org/10.1038/nature08448] [PMID:  19783980] 
[16] 
Rui, L.; Emre, N.C.; Kruhlak, M.J.; Chung, H.J.; Steidl, C.; Slack, G.; Wright, G.W.; Lenz, G.; Ngo, V.N.; Shaffer, A.L.; Xu, W.; Zhao, H.; Yang, Y.; Lamy, L.; Davis, R.E.; Xiao, W.; Powell, J.; Maloney, D.; Thomas, C.J.; Möller, P.; Rosenwald, A.; Ott, G.; Muller-Hermelink, H.K.; Savage, K.; Connors, J.M.; Rimsza, L.M.; Campo, E.; Jaffe, E.S.; Delabie, J.; Smeland, E.B.; Weisenburger, D.D.; Chan, W.C.; Gascoyne, R.D.; Levens, D.; Staudt, L.M. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell,  2010, 18(6), 590-605.
[http://dx.doi.org/10.1016/j.ccr.2010.11.013] [PMID:  21156283] 
[17] 
Yu, H.; Jove, R. The STATs of cancer-new molecular targets come of age. Nat. Rev. Cancer,  2004, 4(2), 97-105.
[http://dx.doi.org/10.1038/nrc1275] [PMID:  14964307] 
[18] 
West, K. CP-690550, a JAK3 inhibitor as an immunosuppressant
for the treatment of rheumatoid arthritis, transplant rejection,
psoriasis and other immune-mediated disorders. Curr. Opin.
Investig. Drugs,  2009, 10(5), 491-504.
[PMID:  19431082] 
[19] 
Aringer, M.; Smolen, J.S. Tumour necrosis factor and other proinflammatory cytokines in systemic lupus erythematosus: A rationale for therapeutic intervention. Lupus,  2004, 13(5), 344-347.
[http://dx.doi.org/10.1191/0961203303lu1024oa] [PMID:  15230290] 
[20] 
Han, R.; Smith, T.J. T helper type 1 and type 2 cytokines exert divergent influence on the induction of prostaglandin E2 and hyaluronan synthesis by interleukin-1beta in orbital fibroblasts: Implications for the pathogenesis of thyroid-associated ophthalmopathy. Endocrinology,  2006, 147(1), 13-19.
[http://dx.doi.org/10.1210/en.2005-1018] [PMID:  16210363] 
[21] 
Dominguez, E.; Mauborgne, A.; Mallet, J.; Desclaux, M.; Pohl, M. SOCS3-mediated blockade of JAK/STAT3 signaling pathway reveals its major contribution to spinal cord neuroinflammation and mechanical allodynia after peripheral nerve injury. J. Neurosci.,  2010, 30(16), 5754-5766.
[http://dx.doi.org/10.1523/JNEUROSCI.5007-09.2010] [PMID:  20410127] 
[22] 
Beurel, E.; Jope, R.S. Differential regulation of STAT family members by glycogen synthase kinase-3. J. Biol. Chem.,  2008, 283(32), 21934-21944.
[http://dx.doi.org/10.1074/jbc.M802481200] [PMID:  18550525] 
[23] 
Min, X.; Ungureanu, D.; Maxwell, S.; Hammarén, H.; Thibault, S.; Hillert, E.K.; Ayres, M.; Greenfield, B.; Eksterowicz, J.; Gabel, C.; Walker, N.; Silvennoinen, O.; Wang, Z. Structural and functional characterization of the JH2 pseudokinase domain of JAK family tyrosine kinase 2 (Tyk2). J. Biol. Chem.,  2015, 290(45), 27261-27270.
[http://dx.doi.org/10.1074/jbc.M115.672048] [PMID:  26359499] 
[24] 
Hammarén, H.M.; Ungureanu, D.; Grisouard, J.; Skoda, R.C.; Hubbard, S.R.; Silvennoinen, O. ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation. Proc. Natl. Acad. Sci. USA,  2015, 112(15), 4642-4647.
[http://dx.doi.org/10.1073/pnas.1423201112] [PMID:  25825724] 
[25] 
Babon, J.J.; Lucet, I.S.; Murphy, J.M.; Nicola, N.A.; Varghese, L.N. The molecular regulation of Janus kinase (JAK) activation. Biochem. J.,  2014, 462(1), 1-13.
[http://dx.doi.org/10.1042/BJ20140712] [PMID:  25057888] 
[26] 
Leonard, W.J.; O’Shea, J.J. Jaks and STATs: Biological implications. Annu. Rev. Immunol.,  1998, 16, 293-322.
[http://dx.doi.org/10.1146/annurev.immunol.16.1.293] [PMID:  9597132] 
[27] 
Johnston, J.A.; Kawamura, M.; Kirken, R.A.; Chen, Y.Q.; Blake, T.B.; Shibuya, K.; Ortaldo, J.R.; McVicar, D.W.; O’Shea, J.J. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature,  1994, 370(6485), 151-153.
[http://dx.doi.org/10.1038/370151a0] [PMID:  8022485] 
[28] 
Nosaka, T.; van Deursen, J.M.; Tripp, R.A.; Thierfelder, W.E.; Witthuhn, B.A.; McMickle, A.P.; Doherty, P.C.; Grosveld, G.C.; Ihle, J.N. Defective lymphoid development in mice lacking Jak3. Science,  1995, 270(5237), 800-802.
[http://dx.doi.org/10.1126/science.270.5237.800] [PMID:  7481769] 
[29] 
Russell, S.M.; Tayebi, N.; Nakajima, H.; Riedy, M.C.; Roberts, J.L.; Aman, M.J.; Migone, T.S.; Noguchi, M.; Markert, M.L.; Buckley, R.H.; O’Shea, J.J.; Leonard, W.J. Mutation of Jak3 in a patient with SCID: Essential role of Jak3 in lymphoid development. Science,  1995, 270(5237), 797-800.
[http://dx.doi.org/10.1126/science.270.5237.797] [PMID:  7481768] 
[30] 
Fridman, J.S.; Scherle, P.A.; Collins, R.; Burn, T.C.; Li, Y.; Li, J.; Covington, M.B.; Thomas, B.; Collier, P.; Favata, M.F.; Wen, X.; Shi, J.; McGee, R.; Haley, P.J.; Shepard, S.; Rodgers, J.D.; Yeleswaram, S.; Hollis, G.; Newton, R.C.; Metcalf, B.; Friedman, S.M.; Vaddi, K. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J. Immunol.,  2010, 184(9), 5298-5307.
[http://dx.doi.org/10.4049/jimmunol.0902819] [PMID:  20363976] 
[31] 
Lu, L.D.; Stump, K.L.; Wallace, N.H.; Dobrzanski, P.; Serdikoff, C.; Gingrich, D.E.; Dugan, B.J.; Angeles, T.S.; Albom, M.S.; Mason, J.L.; Ator, M.A.; Dorsey, B.D.; Ruggeri, B.A.; Seavey, M.M. Depletion of autoreactive plasma cells and treatment of lupus nephritis in mice using CEP-33779, a novel, orally active, selective inhibitor of JAK2. J. Immunol.,  2011, 187(7), 3840-3853.
[http://dx.doi.org/10.4049/jimmunol.1101228] [PMID:  21880982] 
[32] 
Neubert, K.; Meister, S.; Moser, K.; Weisel, F.; Maseda, D.; Amann, K.; Wiethe, C.; Winkler, T.H.; Kalden, J.R.; Manz, R.A.; Voll, R.E. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat. Med.,  2008, 14(7), 748-755.
[http://dx.doi.org/10.1038/nm1763] [PMID:  18542049] 
[33] 
Seif, F.; Khoshmirsafa, M.; Aazami, H.; Mohsenzadegan, M.; Sedighi, G.; Bahar, M. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun. Signal.,  2017, 15(1), 23.
[http://dx.doi.org/10.1186/s12964-017-0177-y] [PMID:  28637459] 
[34] 
Melzner, I.; Weniger, M.A.; Bucur, A.J.; Brüderlein, S.; Dorsch, K.; Hasel, C.; Leithäuser, F.; Ritz, O.; Dyer, M.J.S.; Barth, T.F.E.; Möller, P. Biallelic deletion within 16p13.13 including SOCS-1 in Karpas1106P mediastinal B-cell lymphoma line is associated with delayed degradation of JAK2 protein. Int. J. Cancer,  2006, 118(8), 1941-1944.
[http://dx.doi.org/10.1002/ijc.21485] [PMID:  16287070] 
[35] 
Danese, S.; Mantovani, A. Inflammatory bowel disease and intestinal cancer: A paradigm of the Yin-Yang interplay between inflammation and cancer. Oncogene,  2010, 29(23), 3313-3323.
[http://dx.doi.org/10.1038/onc.2010.109] [PMID:  20400974] 
[36] 
Knüpfer, H.; Preiss, R. Serum interleukin-6 levels in colorectal cancer patients-a summary of published results. Int. J. Colorectal Dis.,  2010, 25(2), 135-140.
[http://dx.doi.org/10.1007/s00384-009-0818-8] [PMID:  19898853] 
[37] 
Corvinus, F.M.; Orth, C.; Moriggl, R.; Tsareva, S.A.; Wagner, S.; Pfitzner, E.B.; Baus, D.; Kaufmann, R.; Huber, L.A.; Zatloukal, K.; Beug, H.; Ohlschläger, P.; Schütz, A.; Halbhuber, K.J.; Friedrich, K. Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia,  2005, 7(6), 545-555.
[http://dx.doi.org/10.1593/neo.04571] [PMID:  16036105] 
[38] 
Morikawa, T.; Baba, Y.; Yamauchi, M.; Kuchiba, A.; Nosho, K.; Shima, K.; Tanaka, N.; Huttenhower, C.; Frank, D.A.; Fuchs, C.S.; Ogino, S. STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers. Clin. Cancer Res.,  2011, 17(6), 1452-1462.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-2694] [PMID:  21310826] 
[39] 
Becker, C.; Fantini, M.C.; Wirtz, S.; Nikolaev, A.; Lehr, H.A.; Galle, P.R.; Rose-John, S.; Neurath, M.F. IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle,  2005, 4(2), 217-220.
[http://dx.doi.org/10.4161/cc.4.2.1413] [PMID:  15655344] 
[40] 
Bromberg, J.; Wang, T.C. Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell,  2009, 15(2), 79-80.
[http://dx.doi.org/10.1016/j.ccr.2009.01.009] [PMID:  19185839] 
[41] 
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell,  2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID:  21376230] 
[42] 
Ihle, J.N. Cytokine receptor signalling. Nature,  1995, 377(6550), 591-594.
[http://dx.doi.org/10.1038/377591a0] [PMID:  7566171] 
[43] 
 Purandare, A.V.; Batt, D.G.; Liu, Q.; Johnson, W.L.; Mastalerz, H.;
Zhang, G.; Zimmermann, K. Carbazole and carboline kinase
inhibitors WO Patent 2010080474, 2010.
[44] 
Kralovics, R.; Passamonti, F.; Buser, A.S.; Teo, S.S.; Tiedt, R.; Passweg, J.R.; Tichelli, A.; Cazzola, M.; Skoda, R.C. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med.,  2005, 352(17), 1779-1790.
[http://dx.doi.org/10.1056/NEJMoa051113] [PMID:  15858187] 
[45] 
Shahmarvand, N.; Nagy, A.; Shahryari, J.; Ohgami, R.S. Mutations in the signal transducer and activator of transcription family of genes in cancer. Cancer Sci.,  2018, 109(4), 926-933.
[http://dx.doi.org/10.1111/cas.13525] [PMID:  29417693] 
[46] 
Shi, M.; He, R.; Feldman, A.L.; Viswanatha, D.S.; Jevremovic, D.; Chen, D.; Morice, W.G. STAT3 mutation and its clinical and histopathologic correlation in T-cell large granular lymphocytic leukemia. Hum. Pathol.,  2018, 73, 74-81.
[http://dx.doi.org/10.1016/j.humpath.2017.12.014] [PMID:  29288042] 
[47] 
Kan, Z.; Zheng, H.; Liu, X.; Li, S.; Barber, T.D.; Gong, Z.; Gao, H.; Hao, K.; Willard, M.D.; Xu, J.; Hauptschein, R.; Rejto, P.A.; Fernandez, J.; Wang, G.; Zhang, Q.; Wang, B.; Chen, R.; Wang, J.; Lee, N.P.; Zhou, W.; Lin, Z.; Peng, Z.; Yi, K.; Chen, S.; Li, L.; Fan, X.; Yang, J.; Ye, R.; Ju, J.; Wang, K.; Estrella, H.; Deng, S.; Wei, P.; Qiu, M.; Wulur, I.H.; Liu, J.; Ehsani, M.E.; Zhang, C.; Loboda, A.; Sung, W.K.; Aggarwal, A.; Poon, R.T.; Fan, S.T.; Wang, J.; Hardwick, J.; Reinhard, C.; Dai, H.; Li, Y.; Luk, J.M.; Mao, M. Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res.,  2013, 23(9), 1422-1433.
[http://dx.doi.org/10.1101/gr.154492.113] [PMID:  23788652] 
[48] 
Igelmann, S.; Neubauer, H.A.; Ferbeyre, G. STAT3 and STAT5 activation in solid cancers. Cancers (Basel),  2019, 11(10), 1428.
[http://dx.doi.org/10.3390/cancers11101428] [PMID:  31557897] 
[49] 
Orlova, A.; Wagner, C.; de Araujo, E.D.; Bajusz, D.; Neubauer, H.A.; Herling, M.; Gunning, P.T.; Keserű, G.M.; Moriggl, R. Direct targeting options for STAT3 and STAT5 in cancer. Cancers (Basel),  2019, 11(12), 1930.
[http://dx.doi.org/10.3390/cancers11121930] [PMID:  31817042] 
[50] 
Kijima, T.; Niwa, H.; Steinman, R.A.; Drenning, S.D.; Gooding, W.E.; Wentzel, A.L.; Xi, S.; Grandis, J.R. STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo. Cell Growth
Differ.,  2002, 13(8), 355-362.
[PMID:  12193474] 
[51] 
Bu, L.L.; Yu, G.T.; Wu, L.; Mao, L.; Deng, W.W.; Liu, J.F.; Kulkarni, A.B.; Zhang, W.F.; Zhang, L.; Sun, Z.J. STAT3 induces immunosuppression by upregulating PD-1/PD-L1 in HNSCC. J. Dent. Res.,  2017, 96(9), 1027-1034.
[http://dx.doi.org/10.1177/0022034517712435] [PMID:  28605599] 
[52] 
Pan, Y.M.; Wang, C.G.; Zhu, M.; Xing, R.; Cui, J.T.; Li, W.M.; Yu, D.D.; Wang, S.B.; Zhu, W.; Ye, Y.J.; Wu, Y.; Wang, S.; Lu, Y.Y. STAT3 signalling drives EZH2 transcriptional activation and mediates poor prognosis in gastric cancer. Mol. Cancer,  2016, 15, 79.
[http://dx.doi.org/10.1186/s12943-016-0561-z] [PMID:  27938379] 
[53] 
Shien, K.; Papadimitrakopoulou, V.A.; Ruder, D.; Behrens, C.; Shen, L.; Kalhor, N.; Song, J.; Lee, J.J.; Wang, J.; Tang, X.; Herbst, R.S.; Toyooka, S.; Girard, L.; Minna, J.D.; Kurie, J.M.; Wistuba, I.I.; Izzo, J.G. JAK1/STAT3 activation through a proinflammatory cytokine pathway leads to resistance to molecularly targeted therapy in non-small cell lung cancer. Mol. Cancer Ther.,  2017, 16(10), 2234-2245.
[http://dx.doi.org/10.1158/1535-7163.MCT-17-0148] [PMID:  28729401] 
[54] 
Lin, X.M.; Chen, H.; Zhan, X.L. MiR-203 regulates JAK-STAT pathway in affecting pancreatic cancer cells proliferation and apoptosis by targeting SOCS3. Eur. Rev. Med. Pharmacol. Sci.,  2019, 23(16), 6906-6913.
[PMID:  31486490] 
[55] 
He, W.; Wu, J.; Shi, J.; Huo, Y.M.; Dai, W.; Geng, J.; Lu, P.; Yang, M.W.; Fang, Y.; Wang, W.; Zhang, Z.G.; Habtezion, A.; Sun, Y.W.; Xue, J. IL22RA1/STAT3 signaling promotes stemness and tumorigenicity in pancreatic cancer. Cancer Res.,  2018, 78(12), 3293-3305.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-3131] [PMID:  29572224] 
[56] 
Escher, T.E.; Lui, A.J.; Geanes, E.S.; Walter, K.R.; Tawfik, O.; Hagan, C.R.; Lewis-Wambi, J. Interaction between MUC1 and STAT1 drives IFITM1 overexpression in aromatase inhibitor-resistant breast cancer cells and mediates estrogen-induced apoptosis. Mol. Cancer Res.,  2019, 17(5), 1180-1194.
[http://dx.doi.org/10.1158/1541-7786.MCR-18-0916] [PMID:  30655323] 
[57] 
Liao, Z.; Lutz, J.; Nevalainen, M.T. Transcription factor Stat5a/b as a therapeutic target protein for prostate cancer. Int. J. Biochem. Cell Biol.,  2010, 42(2), 186-192.
[http://dx.doi.org/10.1016/j.biocel.2009.11.001] [PMID:  19914392] 
[58] 
Li, B.H.; Yang, X.Z.; Li, P.D.; Yuan, Q.; Liu, X.H.; Yuan, J.; Zhang, W.J. IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells. Biochem. Biophys. Res. Commun.,  2008, 369(2), 554-560.
[http://dx.doi.org/10.1016/j.bbrc.2008.02.052] [PMID:  18294957] 
[59] 
Zhao, W.; Jaganathan, S.; Turkson, J. A cell-permeable Stat3 SH2 domain mimetic inhibits Stat3 activation and induces antitumor cell effects in vitro. J. Biol. Chem.,  2010, 285(46), 35855-35865.
[http://dx.doi.org/10.1074/jbc.M110.154088] [PMID:  20807764] 
[60] 
Zhang, X.; Yue, P.; Fletcher, S.; Zhao, W.; Gunning, P.T.; Turkson, J. A novel small-molecule disrupts Stat3 SH2 domain-phosphotyrosine interactions and Stat3-dependent tumor processes. Biochem. Pharmacol.,  2010, 79(10), 1398-1409.
[http://dx.doi.org/10.1016/j.bcp.2010.01.001] [PMID:  20067773] 
[61] 
Redell, M.S.; Ruiz, M.J.; Alonzo, T.A.; Gerbing, R.B.; Tweardy, D.J. Stat3 signaling in acute myeloid leukemia: Ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood,  2011, 117(21), 5701-5709.
[http://dx.doi.org/10.1182/blood-2010-04-280123] [PMID:  21447830] 
[62] 
Fletcher, S.; Singh, J.; Zhang, X.; Yue, P.; Page, B.D.; Sharmeen, S.; Shahani, V.M.; Zhao, W.; Schimmer, A.D.; Turkson, J.; Gunning, P.T. Disruption of transcriptionally active Stat3 dimers with non-phosphorylated, salicylic acid-based small molecules: Potent in vitro and tumor cell activities. ChemBioChem,  2009, 10(12), 1959-1964.
[http://dx.doi.org/10.1002/cbic.200900172] [PMID:  19644994] 
[63] 
Madoux, F.; Koenig, M.; Sessions, H. Modulators of STAT transcription factors for the targeted therapy of cancer (STAT3 inhibitors).Probe Reports from the NIH Molecular Libraries Program; National Center for Biotechnology Information: Bethesda, MD, USA, 2011, pp. 1-20.
[64] 
Nelson, E.A.; Walker, S.R.; Weisberg, E.; Bar-Natan, M.; Barrett, R.; Gashin, L.B.; Terrell, S.; Klitgaard, J.L.; Santo, L.; Addorio, M.R.; Ebert, B.L.; Griffin, J.D.; Frank, D.A. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood,  2011, 117(12), 3421-3429.
[http://dx.doi.org/10.1182/blood-2009-11-255232] [PMID:  21233313] 
[65] 
Nelson, E.A.; Sharma, S.V.; Settleman, J.; Frank, D.A. A chemical biology approach to developing STAT inhibitors: Molecular strategies for accelerating clinical translation. Oncotarget,  2011, 2(6), 518-524.
[http://dx.doi.org/10.18632/oncotarget.296] [PMID:  21680956] 
[66] 
Li, W.X. Canonical and non-canonical JAK-STAT signaling. Trends Cell Biol.,  2008, 18(11), 545-551.
[http://dx.doi.org/10.1016/j.tcb.2008.08.008] [PMID:  18848449] 
[67] 
Regis, G.; Pensa, S.; Boselli, D.; Novelli, F.; Poli, V. Ups and downs: The STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling. Semin. Cell Dev. Biol.,  2008, 19(4), 351-359.
[http://dx.doi.org/10.1016/j.semcdb.2008.06.004] [PMID:  18620071] 
[68] 
Kumar, A.; Commane, M.; Flickinger, T.W.; Horvath, C.M.; Stark, G.R. Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science,  1997, 278(5343), 1630-1632.
[http://dx.doi.org/10.1126/science.278.5343.1630] [PMID:  9374464] 
[69] 
Zhang, Q.; Wang, H.Y.; Marzec, M.; Raghunath, P.N.; Nagasawa, T.; Wasik, M.A. STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc. Natl. Acad. Sci. USA,  2005, 102(19), 6948-6953.
[http://dx.doi.org/10.1073/pnas.0501959102] [PMID:  15870198] 
[70] 
Zhang, Q.; Wang, H.Y.; Liu, X.; Wasik, M.A. STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression. Nat. Med.,  2007, 13(11), 1341-1348.
[http://dx.doi.org/10.1038/nm1659] [PMID:  17922009] 
[71] 
Reich, N.C. STAT3 revs up the powerhouse. Sci. Signal.,  2009, 2(90), pe61.
[http://dx.doi.org/10.1126/scisignal.290pe61] [PMID:  19797267] 
[72] 
Walker, S.R.; Chaudhury, M.; Nelson, E.A.; Frank, D.A. Microtubule-targeted chemotherapeutic agents inhibit signal transducer and activator of transcription 3 (STAT3) signaling. Mol. Pharmacol.,  2010, 78(5), 903-908.
[http://dx.doi.org/10.1124/mol.110.066316] [PMID:  20693278] 
[73] 
Hurwitz, H.I.; Uppal, N.; Wagner, S.A.; Bendell, J.C.; Beck, J.T.; Wade, S.M., III; Nemunaitis, J.J.; Stella, P.J.; Pipas, J.M.; Wainberg, Z.A.; Manges, R.; Garrett, W.M.; Hunter, D.S.; Clark, J.; Leopold, L.; Sandor, V.; Levy, R.S. Randomized, double-blind, phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. J. Clin. Oncol.,  2015, 33(34), 4039-4047.
[http://dx.doi.org/10.1200/JCO.2015.61.4578] [PMID:  26351344] 
[74] 
Seol, M.A.; Kim, J.H.; Oh, K.; Kim, G.; Seo, M.W.; Shin, Y.K.; Sim, J.H.; Shin, H.M.; Seo, B.Y.; Lee, D.S.; Ku, J.L.; Han, I.; Kang, I.; Park, S.I.; Kim, H.R. Interleukin-7 contributes to the invasiveness of prostate cancer cells by promoting epithelial-mesenchymal transition. Sci. Rep.,  2019, 9(1), 6917.
[http://dx.doi.org/10.1038/s41598-019-43294-4] [PMID:  31061414] 
[75] 
Changelian, P.S.; Flanagan, M.E.; Ball, D.J.; Kent, C.R.; Magnuson, K.S.; Martin, W.H.; Rizzuti, B.J.; Sawyer, P.S.; Perry, B.D.; Brissette, W.H.; McCurdy, S.P.; Kudlacz, E.M.; Conklyn, M.J.; Elliott, E.A.; Koslov, E.R.; Fisher, M.B.; Strelevitz, T.J.; Yoon, K.; Whipple, D.A.; Sun, J.; Munchhof, M.J.; Doty, J.L.; Casavant, J.M.; Blumenkopf, T.A.; Hines, M.; Brown, M.F.; Lillie, B.M.; Subramanyam, C.; Shang-Poa, C.; Milici, A.J.; Beckius, G.E.; Moyer, J.D.; Su, C.; Woodworth, T.G.; Gaweco, A.S.; Beals, C.R.; Littman, B.H.; Fisher, D.A.; Smith, J.F.; Zagouras, P.; Magna, H.A.; Saltarelli, M.J.; Johnson, K.S.; Nelms, L.F.; Des Etages, S.G.; Hayes, L.S.; Kawabata, T.T.; Finco-Kent, D.; Baker, D.L.; Larson, M.; Si, M.S.; Paniagua, R.; Higgins, J.; Holm, B.; Reitz, B.; Zhou, Y.J.; Morris, R.E.; O’Shea, J.J.; Borie, D.C. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science,  2003, 302(5646), 875-878.
[http://dx.doi.org/10.1126/science.1087061] [PMID:  14593182] 
[76] 
Plimack, E.R.; Lorusso, P.M.; McCoon, P.; Tang, W.; Krebs, A.D.; Curt, G.; Eckhardt, S.G. AZD1480: A phase I study of a novel JAK2 inhibitor in solid tumors. Oncologist,  2013, 18(7), 819-820.
[http://dx.doi.org/10.1634/theoncologist.2013-0198] [PMID:  23847256] 
[77] 
Hedvat, M.; Huszar, D.; Herrmann, A.; Gozgit, J.M.; Schroeder, A.; Sheehy, A.; Buettner, R.; Proia, D.; Kowolik, C.M.; Xin, H.; Armstrong, B.; Bebernitz, G.; Weng, S.; Wang, L.; Ye, M.; McEachern, K.; Chen, H.; Morosini, D.; Bell, K.; Alimzhanov, M.; Ioannidis, S.; McCoon, P.; Cao, Z.A.; Yu, H.; Jove, R.; Zinda, M. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell,  2009, 16(6), 487-497.
[http://dx.doi.org/10.1016/j.ccr.2009.10.015] [PMID:  19962667] 
[78] 
Su, Q.; Banks, E.; Bebernitz, G.; Bell, K.; Borenstein, C.F.; Chen, H.; Chuaqui, C.E.; Deng, N.; Ferguson, A.D.; Kawatkar, S.; Grimster, N.P.; Ruston, L.; Lyne, P.D.; Read, J.A.; Peng, X.; Pei, X.; Fawell, S.; Tang, Z.; Throner, S.; Vasbinder, M.M.; Wang, H.; Winter-Holt, J.; Woessner, R.; Wu, A.; Yang, W.; Zinda, M.; Kettle, J.G. Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpi-perazin-1-yl)propenamide (AZD4205) as a potent and selective Janus kinase 1 inhibitor. J. Med. Chem.,  2020, 63(9), 4517-4527.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01392] [PMID:  32297743] 
[79] 
Iwamaru, A.; Szymanski, S.; Iwado, E.; Aoki, H.; Yokoyama, T.; Fokt, I.; Hess, K.; Conrad, C.; Madden, T.; Sawaya, R.; Kondo, S.; Priebe, W.; Kondo, Y. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene,  2007, 26(17), 2435-2444.
[http://dx.doi.org/10.1038/sj.onc.1210031] [PMID:  17043651] 
[80] 
Verstovsek, S.; Manshouri, T.; Quintás-Cardama, A.; Harris, D.; Cortes, J.; Giles, F.J.; Kantarjian, H.; Priebe, W.; Estrov, Z. WP1066, a novel JAK2 inhibitor, suppresses proliferation and induces apoptosis in erythroid human cells carrying the JAK2 V617F mutation. Clin. Cancer Res.,  2008, 14(3), 788-796.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-0524] [PMID:  18245540] 
[81] 
Regenbogen, T.; Chen, L.; Trinkaus, K.; Wang-Gillam, A.; Tan, B.R.; Amin, M.; Pedersen, K.S.; Park, H.; Suresh, R.; Lim, K.H.; Ratchford, E.; Brown, A.; Lockhart, A.C. Pacritinib to inhibit JAK/STAT signaling in refractory metastatic colon and rectal cancer. J. Gastrointest. Oncol.,  2017, 8(6), 985-989.
[http://dx.doi.org/10.21037/jgo.2017.08.16] [PMID:  29299358] 
[82] 
Chan, E.; Luwor, R.; Burns, C.; Kannourakis, G.; Findlay, J.K.; Ahmed, N. Momelotinib decreased cancer stem cell associated tumor burden and prolonged disease-free remission period in a mouse model of human ovarian cancer. Oncotarget,  2018, 9(24), 16599-16618.
[http://dx.doi.org/10.18632/oncotarget.24615] [PMID:  29682172] 
[83] 
Pardanani, A.; Lasho, T.; Smith, G.; Burns, C.J.; Fantino, E.; Tefferi, A. CYT387, a selective JAK1/JAK2 inhibitor: In vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia Vera patients. Leukemia,  2009, 23(8), 1441-1445.
[http://dx.doi.org/10.1038/leu.2009.50] [PMID:  19295546] 
[84] 
Menet, C.J.; Fletcher, S.R.; Van Lommen, G.; Geney, R.; Blanc, J.; Smits, K.; Jouannigot, N.; Deprez, P.; van der Aar, E.M.; Clement-Lacroix, P.; Lepescheux, L.; Galien, R.; Vayssiere, B.; Nelles, L.; Christophe, T.; Brys, R.; Uhring, M.; Ciesielski, F.; Van Rompaey, L. Triazolopyridines as selective JAK1 inhibitors: From hit identification to GLPG0634. J. Med. Chem.,  2014, 57(22), 9323-9342.
[http://dx.doi.org/10.1021/jm501262q] [PMID:  25369270] 
[85] 
Zhao, C.; Khadka, D.B.; Cho, W.J. Insights into the structural features essential for JAK2 inhibition and selectivity. Curr. Med. Chem.,  2016, 23(13), 1331-1355.
[http://dx.doi.org/10.2174/0929867323666160405112615] [PMID:  27048338] 
[86] 
Burns, C.J.; Bourke, D.G.; Andrau, L. X, Bu.; Charman, SA; Donohue, AC; Fantino, E; Farrugia, M.; Feutrill, J. T.; Joffe, M.; Kling, M. R.; Kurek, M.; Nero, T. L.; Nguyen, T.; Palmer, J. T.; Phillips, I.; Shackleford, D. M.; Sikanyika, H.; Styles, M.; Su, S.; Wilks, A. F. Phenyl-amino-pyrimidines as inhibitors of Janus kinases (JAKs). Bioorg. Med. Chem. Lett.,  2009, 19(20), 5887-5892.
[http://dx.doi.org/10.1016/j.bmcl.2009.08.071] [PMID:  19762238] 
[87] 
Hanan, E.J.; van Abbema, A.; Barrett, K.; Blair, W.S.; Blaney, J.; Chang, C.; Eigenbrot, C.; Flynn, S.; Gibbons, P.; Hurley, C.A.; Kenny, J.R.; Kulagowski, J.; Lee, L.; Magnuson, S.R.; Morris, C.; Murray, J.; Pastor, R.M.; Rawson, T.; Siu, M.; Ultsch, M.; Zhou, A.; Sampath, D.; Lyssikatos, J.P. Discovery of potent and selective pyrazolopyrimidine Janus kinase 2 inhibitors. J. Med. Chem.,  2012, 55(22), 10090-10107.
[http://dx.doi.org/10.1021/jm3012239] [PMID:  23061660] 
[88] 
Pissot-Soldermann, C.; Gerspacher, M.; Furet, P.; Gaul, C.; Holzer, P.; McCarthy, C.; Radimerski, T.; Regnier, C.H.; Baffert, F.; Drueckes, P.; Tavares, G.A.; Vangrevelinghe, E.; Blasco, F.; Ottaviani, G.; Ossola, F.; Scesa, J.; Reetz, J. Discovery and SAR of
potent, orally available 2,8-diaryl-quinoxalines as a new class of
JAK2 inhibitors. Bioorg. Med. Chem. Lett.,  2010, 20(8), 2609-2613.
[http://dx.doi.org/10.1016/j.bmcl.2010.02.056] [PMID:  20231096] 
Rights & Permissions Print Cite
Article Metrics
23
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1568009622666220301105214	Print ISSN 1568-0096
Publisher Name Bentham Science Publisher	Online ISSN 1873-5576
当代肿瘤药物靶点

Janus 激酶抑制剂在癌症治疗中的新作用

摘要

图形摘要

当代肿瘤药物靶点

Janus 激酶抑制剂在癌症治疗中的新作用

摘要 Play Pause

图形摘要

Related Journals

Related Books

摘要
