Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2010, Vol. 4 Issue (1) : 46-53     DOI: 10.1007/s11684-010-0010-0
Research articles |
Mitogen-activated protein kinase pathway inhibitors: inhibitors for diseases?
Xu WANG MS1,Xiao-Wei GONG MD, PhD2,Yong JIANG MD, PhD2,Yu-Hua LI PhD3,
1.College of Life Science, Northeast Forestry University, Harbin 150040, China;Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China; 2.Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China; 3.College of Life Science, Northeast Forestry University, Harbin 150040, China;
Download: PDF(258 KB)  
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract  Mitogen-activated protein kinase (MAPK) signaling pathway, one of the most important signaling pathways in eukaryotic organism, is involved in multiple cellular events such as cell growth, differentiation, and apoptosis. MAPK is of great importance to the normal function of organisms, while its dysfunction results in various diseases. So far, inhibitors specifically against each subfamilies of MAP kinase have been developed, while more endeavors are needed to discover the compounds selectively targeting a particular subfamily member. Most of the kinase inhibitors exert their functions in an ATP-competitive way or a non-ATP-competitive way. Further studies on the effective mechanism of the MAPK inhibitors and their therapeutic roles in the treatment of diseases are helpful for the illumination of MAP kinase function, the development of novel inhibitors, and the therapy of diseases caused by the dysfunction of the MAPK pathway.
Keywords mitogen-activated protein kinase      drug target      inhibitor      signal transduction      disease      
Issue Date: 05 March 2010
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-010-0010-0     OR     http://academic.hep.com.cn/fmd/EN/Y2010/V4/I1/46
Widmann C, Gibson S, Jarpe M B, Johnson G L. Mitogen-activated protein kinase: conservation of a three-kinasemodule from yeast to human. Physiol Rev, 1999, 79(1): 143–180
Gong X W, Jiang Y. Progressesin mitogen-activated protein kinase-activated protein kinases. Shengwuhuaxue Yu Shengwuwuli Jinzhan, 2007, 34(7): 1–7 (in Chinese)
Gong X W, Wei J, Li Y S, Cheng W W, Deng P, Jiang Y. Involvement of p38 mitogen-activated protein kinase inthe regulation of platelet-derived growth factor-induced cell migration. Front Med China, 2007, 1(3): 248–252
Jiang Y, Chen C, Li Z, Guo W, Gegner J A, Lin S, Han J. Characterization of the structureand function of a new mitogen-activated protein kinase (p38beta). J Biol Chem, 1996, 271(30): 17920–17926
Ivanenkov Y A, Balakin K V, Tkachenko S E. New approaches to the treatmentof inflammatory disease: focus on small molecule inhibitors of signaltransduction pathways. Drugs R D, 2008, 9(6): 397–434
Adcock I M, Caramori G, Chung K F. New targets for drug developmentin asthma. Lancet, 2008, 372(9643): 1073–1087
Smith R A, Dumas J, Adnane L, Wilhelm S M. Recent advances in the research and development of RAF kinase inhibitors. Curr Top Med Chem, 2006, 6(11): 1071–1089
VanScyoc W S, Holdgate G A, Sullivan J E, Ward W H. Enzyme kinetics and binding studies on inhibitors ofMEK protein kinase. Biochemistry, 2008, 47(17): 5017–5027
Ohori M, Takeuchi M, Maruki R, Nakajima H, Miyake H. FR180204,a novel and selective inhibitor of extracellular signal-regulatedkinase, ameliorates collagen-induced arthritis in mice. Naunyn Schmiedebergs Arch Pharmacol, 2007, 374(4): 311–316
Kelemen B R, Hsiao K, Goueli S A. Selective invivo inhibition of mitogen-activated protein kinase activationusing cell-permeable peptides. J Biol Chem, 2002, 277(10): 8741–8748
Bogoyevitch M A, Boehm I, Oakley A, Ketterman A J, Barr R K. Targeting the JNK MAPK cascadefor inhibition: basic science and therapeutic potential. Biochim Biophys Acta, 2004, 1697(1―2): 89–101
Bogoyevitch M A, Arthur P G. Inhibitors of c-Jun N-terminal kinases: JuNK no more? Biochim Biophys Acta, 2008, 1784(1): 76–93
Scapin G, Patel S B, Lisnock J, Becker J W, LoGrasso P V. The structure of JNK3 incomplex with small molecule inhibitors. Chem Biol, 2003, 10(8): 705–712
Carboni S, Boschert U, Gaillard P, Gotteland J P, Gillon J Y, Vitte P A. AS601245, a c-Jun NH2-terminalkinase (JNK) inhibitor, reduces axon/dendrite damage and cognitivedeficits after global cerebral ischemia in gerbils. Br J Pharmacol, 2008, 153(1): 157–163
Barr R K, Boehm I, Attwood P V, Watt P M, Bogoyevitch M A. The critical features andthe mechanism of inhibition of a kinase interaction motif-based peptideinhibitor of JNK. J Biol Chem, 2004, 279(35): 36327–36338
Holzberg D, Knight C G, Dittrich-Breiholz O, Schneider H, Dorrie A, Hoffmann E, Resch K, Kracht M. Disruptionof the c-JUN-JNK complex by a cell-permeable peptide containing thec-JNK delta domain induces apoptosis and affects a distinct set ofinterleukin-1-induced inflammatory genes. J Biol Chem, 2003, 278(41): 40213–40223
Argast G M, Fausto N, Campbell J S. Inhibition of RIP2/Rick/CARDIAKactivity by pyridinyl imidazole inhibitors of p38 MAPK. Mol Cell Biochem, 2005, 268(1―2): 129–140
Fitzgerald C E, Patel S B, Becker J W, Cameron P M, Zaller D, Pikounis V B, O’Keefe S J, Scapin G. Structural basis for p38αMAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity. Nat Struct Biol, 2003, 10(9): 764–769
Cuenda A, Rousseau S. p38MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta, 2007, 1773(8): 1358–1375
Bullington J, Argentieri D, Averill K, Carter D, Cavender D, Fahmy B, Fan X, Hall D, Heintzelman G, Jackson P, Leung W P, Li X, Ling P, Olini G, Razler T, Reuman M, Rupert K, Russell R, Siekierka J, Wadsworth S, Wolff R, Xiang B, Zhang Y M. Inhibitors of unactivated p38 MAP kinase. Bioorg Med Chem Lett, 2006, 16(23): 6102–6106
Pargllis C, Tong L, Churchill L, Cirillo P F, Gilmore T, Graham A G, Grob P M, Hickey E R, Moss N, Pav S, Regan J. Inhibition of p38 MAP Kinase by utilizing a novel allostericbinding site. Nat Struct Biol, 2002, 9(4): 268–272
Kuma Y, Sabio G, Bain J, Shpiro N, Marquez R, Cuenda A. BIRB796 inhibits all p38 MAPK isoforms in vivo and invivo. J Biol Chem, 2005, 280(20): 19472–19479
Nishimoto S, Nishida E. MAPKsignaling: ERK5 versus ERK1/2. EMBO Rep, 2006, 7(8): 782–786
Davies S P, Reddy H, Caivano M, Cohen P. Specificityand mechanism of action of some commonly used protein kinase inhibitors. Biochem J, 2000, 351(1): 95–105
Gaestel M. MAPKAP kinases– MKs– two's company, three's a crowd. Nat Rev Mol Cell Biol, 2006, 7(2): 120–130
Noble M E, Endicott J A, Johnson L N. Protein kinase inhibitors:insights into drug design from structure. Science, 2004, 303(5665): 1800–1805
Force T, Kuida K, Namchuk M, Parang K, Kyriakis J M. Inhibitors of protein kinasesignaling pathways: emerging therapies for cardiovascular disease. Circulation, 2004, 109(10): 1196–1205
Wang Z, Harkins P C, Ulevitch R J, Han J, Cobb M H, Goldsmith E J. The structure of mitogen-activatedprotein kinase p38 at 2.1Å resolution. Proc Natl Acad Sci U S A, 1997, 94(6): 2327–2332
Wang Z, Canagarajah B J, Boehm J C, Kassisa S, Cobb M H, Young P R, Abdel-Mequid S, Adams J L, Goldsmith E J. Structural basis of inhibitor selectivity in MAP kinases. Structure, 1998, 6(9): 1117–1128
Eyers P A, Craxton M, Morrice N, Cohen P, Goedert M. Conversionof SB 203580-insensitive MAP kinase family members to drug-sensitiveforms by a single amino-acid substitution. Chem Biol, 1998, 5(6): 321–328
Gum R J, McLaughlin M M, Kumar S, Wang Z, Bower M J, Lee J C, Adams J L, Livi G P, Goldsmith E J, Young P R. Acquisitionof sensitivity of stress-activated protein kinase to the p38 inhibitor,SB 203580, by alteration of one or more amino acids within the ATPbinding pocket. J Biol Chem, 1998, 273(25): 15605–15610
Lisnock J, Tebben A, Frantz B, O’Neill E A, Croft G, O’Keefe S J, Li B, Hacker C, de Laszlo S, Smith A, Libby B, Liverton N, Hermes J, LoGrasso P. Molecular basis for p38 proteinkinase inhibitor specificity. Biochemistry, 1998, 37(47): 16573–16581

doi: 10.1021/bi981591x
Sack J S, Kish K F, Pokross M, Xie D, Duke G J, Tredup J A, Kiefer S E, Newitt J A. Structural basis for thehigh-affinity binding of pyrrolotriazine inhibitors of p38 MAP kinase. Acta Crystallogr D Biol Crystallogr, 2008, 64(7): 705–710

doi: 10.1107/S0907444908010032
Abraham R T, Acquarone M, Andersen A, Asensi A, Belle R, Berger F, Berqounioux C, Brunn G, Buquet-Fagot C, Fagot D. Cellular effectsof olomoucine, an inhibitor of cyclin-dependent kinase. Biol Cell, 1995, 83(2―3): 105–120

doi: 10.1016/0248-4900(96)81298-6
Akella R, Moon T M, Goldsmith E J. Unique MAP kinase bindingsites. Biochim Biophys Acta, 2008, 1784(1): 48–55
Heo Y S, Kim S K, Seo C I, Kim Y K, Sung B J, Lee H S, Lee J I, Park S Y, Kim J H, Hwang K Y, Hyun Y L, Jeon Y H, Ro S, Cho J M, Lee T G, Yang C H. Structural basis for the selective inhibition of JNK1 by the scaffoldingprotein JIP1 and SP600125. EMBO J, 2004, 23(11): 2185–2195

doi: 10.1038/sj.emboj.7600212
Salh B. c-Jun N-terminal kinases as potential therapeutic targets. Expert Opin Ther Targets, 2007, 11(10): 1339–1353

doi: 10.1517/14728222.11.10.1339
Allen L F, Sebolt-Leopold J, Meyer M B. CI-1040 (PD184352), a targetedsignal transduction inhibitor of MEK (MAPKK). Semin Oncol, 2003, 30(5 suppl 16): 105–116

doi: 10.1053/j.seminoncol.2003.08.012
Shaw D, Wang S M, Villasenor A G, Tsing S, Walter D, Browner M F, Barnett J, Kuqlstatter A. Thecrystal structure of JNK2 reveals conformational flexibility in theMAP kinase insert and indicates its involvement in the regulationof catalytic activity. J Mol Biol, 2008, 383(4): 885–893

doi: 10.1016/j.jmb.2008.08.086
Anqell R M, Anqell T D, Bamborough P, Bamford M J, Chung C W, Cockerill S G, Flack S S, Jones K L, Laine D I, Longstaff T, Ludbrook S, Pearson R, Smith K J, Smee P A, Somers D O, Walker A L. Biphenyl amide p38 kinaseinhibitors 4: DFG-in and DFG-out binding modes. Bioorg Med Chem Lett, 2008, 18(15): 4433–4437

doi: 10.1016/j.bmcl.2008.06.028
Moss N, Breitfelder S, Betageri R, Cirillo P F, Fadra T, Hickey E R, Kirrane T, Kroe R R, Madwed J, Nelson R M, Pargellis C A, Qian K C, Regan J, Swinamer A, Torcellini C. Newmodifications to the area of pyrazole-naphthyl urea based p38 MAPkinase inhibitors that bind to the adenine/ATP site. Bioorg Med Chem Lett, 2007, 17(15): 4242–4247

doi: 10.1016/j.bmcl.2007.05.042
Grande M T, López-Novoa J M. Therapeutical relevance of MAP-kinase inhibitors in renal diseases:current knowledge and future clinical perspectives. Curr Med Chem, 2008, 15(20): 2054–2070

doi: 10.2174/092986708785132889
Sebolt-Leopold J S. Development of anticancer drugs targetingthe MAP kinase pathway. Oncogene, 2000, 19(56): 6594–6599

doi: 10.1038/sj.onc.1204083
Malemud C J. Inhibitors of stress-activated protein/mitogen-activatedprotein kinase pathways. Curr Opin Pharmacol, 2007, 7(3): 339–343

doi: 10.1016/j.coph.2006.11.012
Gollob J A, Wilhelm S, Carter C, Kelley S L. Role of Raf kinase in cancer: therapeutic potential oftargeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol, 2006, 33(4): 392–406

doi: 10.1053/j.seminoncol.2006.04.002
Roberts P J, Der C J. Targetingthe Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatmentof cancer. Oncogene, 2007, 26(22): 3291–3310

doi: 10.1038/sj.onc.1210422
Arslan M A, Kutuk O, Basaga H. Protein kinases as drug targets in cancer. Curr Cancer Drug Targets, 2006, 6(7): 623–634

doi: 10.2174/156800906778742479
Schuh K, Pahl A. Inhibitionof the MAP kinase ERK protects from lipopolysaccharide-induced lunginjury. Biochem Pharmacol, 2009, 77(12): 1827–1834

doi: 10.1016/j.bcp.2009.03.012
Chung E J, Brown A P, Asano H, Mandler M, Burgan W E, Carter D, Camphausen K, Citrin D. Invivo and in vivo radiosensitizationwith AZD6244 (ARRY-142886), an inhibitor of mitogen-activated proteinkinase/extracellular signal-regulated kinase 1/2 kinase. Clin Cancer Res, 2009, 15(9): 3050–3057

doi: 10.1158/1078-0432.CCR-08-2954
Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumorangiogenesis, and induces tumor cell apoptosis in hepatocellular carcinomamodel PLC/PRF/5. Cancer Res, 2006, 66(24): 11851–11858

doi: 10.1158/0008-5472.CAN-06-1377
Apostol B L, Simmons D A, Zuccato C, Illes K, Pallos J, Conforti P, Ramos C, Roarke M, Kathuria S, Cattaneo E, Marsh J L, Thompson L M. CEP-1347 reduces mutant huntingtin-associatedneurotoxicity and restores BDNF levels in R6/2 mice. Mol Cell Neurosci, 2008, 39(1): 8–20

doi: 10.1016/j.mcn.2008.04.007
de Borst M H, Prakash J, Sandovici M, Klok P A, Hamming I, Kok R J, Navis G, van Goor H. c-JunNH2-terminal kinase is crucially involved in renal tubule-interstitialinflammation. J Pharmacol Exp Ther, 2009, 331(3): 896–905

doi: 10.1124/jpet.109.154179
Carboni S, Boschert U, Gaillard P, Gotteland J P, Gillon J Y, Vitte P A. AS601245, a c-Jun NH2-terminalkinase (JNK) inhibitor, reduces axon/dendrite damage and cognitivedeficits after global cerebral ischemia in gerbils. Br J Pharmacol, 2008, 153(1): 157–163

doi: 10.1038/sj.bjp.0707574
Barone F C, Irving E A, Ray A M, Lee J C, Kassis S, Kumar S, Badger A M, Legos J J, Erhardt J A, Ohlstein E H, Hunter A J, Harrison D C, Philpott K, Smith B R, Adams J L, Parsons A A. Inhibition of p38 mitogen-activated protein kinase provides neuroprotectionin cerebral focal ischemia. Med Res Rev, 2001, 21(2): 129–145

doi: 10.1002/1098-1128(200103)21:2<129::AID-MED1003>3.0.CO;2-H
Medicherla S, Fitzgerald M F, Spicer D, Woodman P, Ma J Y, Kapoun A M, Chakaravaty S, Dugar S, Protter A A, Higgins L S. p38alpha-selective mitogen-activated protein kinase inhibitor SD-282reduces inflammation in a subchronic model of tobacco smoke-inducedairway inflammation. J Pharmacol Exp Ther, 2008, 324(3): 921–929

doi: 10.1124/jpet.107.127092
Genovese M C. Inhibition of p38: has the fat lady sung? Arthritis Rheum, 2009, 60(2): 317–320

doi: 10.1002/art.24264
Tripathi B K, Stepp M A, Gao C Y, Zelenka P S. The Cdk5 inhibitor olomoucine promotes corneal debridement woundclosure in vivo. Mol Vis, 2008, 14(1): 542–549
Bogoyevitch M A, Boehm I, Oakley A, Ketterman A J, Barr R K. Targeting the JNK MAPK cascadefor inhibition: basic science and therapeutic potential. Biochim Biophys Acta, 2004, 1697(1―2): 89–101
Hall-Jackson C A, Goedert M, Hedge P, Cohen P. Effect of SB203580 on the activity of c-Raf in vitroand in vivo. Oncogene, 1999, 18(12): 2047–2054

doi: 10.1038/sj.onc.1202603
Katsanakis K D, Owen C, Zoumpourlis V. JNK and ERK signaling pathwaysin multistage mouse carcinogenesis: studies in the inhibition of signalingcascades as a means to understand their invivo biological role. AnticancerRes, 2002, 22(2A): 755–759
[1] Fatemeh Mehravar,Soheil Rafiee,Behnaz Bazrafshan,Mahmoud Khodadost. Prevalence of asthma symptoms in Golestan schoolchildren aged 6–7 and 13–14 years in Northeast Iran[J]. Front. Med., 2016, 10(3): 345-350.
[2] Jiansong Huang,Yulan Zhou,Xiaoyu Su,Yuanjing Lyu,Lanlan Tao,Xiaofeng Shi,Ping Liu,Zhangbiao Long,Zheng Ruan,Bing Xiao,Wenda Xi,Quansheng Zhou,Jianhua Mao,Xiaodong Xi. Roles of integrin β3 cytoplasmic tail in bidirectional signal transduction in a trans-dominant inhibition model[J]. Front. Med., 2016, 10(3): 311-319.
[3] Chunsong Hu,Qinghua Wu. Health: a dream from reality to the future[J]. Front. Med., 2016, 10(2): 233-235.
[4] Marijke A. de Vries,Arash Alipour,Erwin Birnie,Andrew Westzaan,Selvetta van Santen,Ellen van der Zwan,Anho H. Liem,Noëlle van der Meulen,Manuel Castro Cabezas. Coronary leukocyte activation in relation to progression of coronary artery disease[J]. Front. Med., 2016, 10(1): 85-90.
[5] Xueshan Bu,Lei Yang,Yunxia Zuo. Efficacy and safety of perioperative parecoxib for acute postoperative pain treatment in children: a meta-analysis[J]. Front. Med., 2015, 9(4): 496-507.
[6] Lixia Gan,Wei Xiang,Bin Xie,Liqing Yu. Molecular mechanisms of fatty liver in obesity[J]. Front. Med., 2015, 9(3): 275-287.
[7] Jeffrey H. Mandel,Christine Wendt,Charles Lo,Guangbiao Zhou,Marshall Hertz,Gurumurthy Ramachandran. Ambient air pollution and lung disease in China: health effects, study design approaches and future research[J]. Front. Med., 2015, 9(3): 392-400.
[8] Nidhya Ganesan,Marie Moses Ambroise,Anita Ramdas,King Herald Kisku,Kulwant Singh,Renu G’ Boy Varghese. Pulmonary alveolar microlithiasis: an interesting case report with systematic review of Indian literature[J]. Front. Med., 2015, 9(2): 229-238.
[9] Farhad Sahebjam,John M. Vierling. Autoimmune hepatitis[J]. Front. Med., 2015, 9(2): 187-219.
[10] Lei Han,Jing Yang,Xiuwen Wang,Dan Li,Ling Lv,Bin Li. Th17 Cells in autoimmune diseases[J]. Front. Med., 2015, 9(1): 10-19.
[11] Amma Owusu-Ansah,Sung Hee Choi,Agne Petrosiute,John J. Letterio,Alex Yee-Chen Huang. Triterpenoid inducers of Nrf2 signaling as potential therapeutic agents in sickle cell disease: a review[J]. Front. Med., 2015, 9(1): 46-56.
[12] David P. Taggart. Contemporary coronary artery bypass grafting[J]. Front. Med., 2014, 8(4): 395-398.
[13] Feng Wang,Chen Chen,Daowen Wang. Circulating microRNAs in cardiovascular diseases: from biomarkers to therapeutic targets[J]. Front. Med., 2014, 8(4): 404-418.
[14] Minghang Wang,Jiansheng Li,Suyun Li,Yang Xie. Effects of comprehensive therapy based on traditional Chinese medicine patterns on older patients with chronic obstructive pulmonary disease: a subgroup analysis from a four-center, randomized, controlled study[J]. Front. Med., 2014, 8(3): 368-375.
[15] Paul J. Pockros. Advances in newly developing therapy for chronic hepatitis C virus infection[J]. Front. Med., 2014, 8(2): 166-174.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed