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Chemical Compound Review

CHEMBL10     4-[5-(4-fluorophenyl)-2-(4...

Synonyms: Tocris-1202, Tocris-1402, cc-50, SureCN95208, Kinome_2521, ...
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Disease relevance of Tocris-1202

  • Bleb formation but not apoptosis was blocked by extremely low concentrations of the actin polymerization inhibitor cytochalasin D or by the SAPK2 inhibitor SB203580, indicating that the two processes are not in the same linear cascade [1].
  • Administering SB 203580 before ischemia and during reperfusion completely inhibited p38 MAPK activation and exerted the most cardioprotective effects [2].
  • IL-8 secretion was inhibited by pertussis toxin and a selective p38 kinase inhibitor, SB203580 [3].
  • Treatment of melanoma cells with SB203580, a selective inhibitor of the p38 mitogen-activated protein kinase (MAPK) pathway, effectively inhibited Ad.mda-7-induced apoptosis [4].
  • Lymphoma growth was also inhibited in SB203580-treated NOD-SCID mice [5].

Psychiatry related information on Tocris-1202

  • (2) Compared with icv saline group, the motor activity was significantly decreased in SB203580 group with maximal changes (-7.6+/-1.1) counts/min after footshock [6].

High impact information on Tocris-1202

  • A specific inhibitor of p38 MAP kinase, SB203580, abolished the stress-inducible in vivo phosphorylation of CHOP [7].
  • Under isotonic conditions, there was constitutive activity of p38 MAP kinase that was selectively inhibited by SB203580 [8].
  • SB203580 also blocked monocyte necrosis and IL-1beta release caused by toxin A but not by other toxins [9].
  • Finally, in mouse ileum, SB203580 prevented toxin A-induced neutrophil recruitment by 92% and villous destruction by 90% [9].
  • The p38 inhibitor SB203580 led to a reduction of approximately 60% in strain-activated human BNP (hBNP) promoter activity [10].

Chemical compound and disease context of Tocris-1202


Biological context of Tocris-1202

  • This enhancement was reduced by inhibition of p38 with SB203580, suggesting that p38 up-regulation participates in HS-induced enhancements of degranulation [16].
  • Concomitant treatment with SB203580, a p38 MAP kinase inhibitor, diminished caspase induction and protected SH-SY5Y cells and primary cultures of cortical neurons from NO-induced cell death, whereas the caspase inhibitor zVAD-fmk did not provide significant protection [17].
  • Under the same conditions, SB203580 also completely inhibited TNF-induced synthesis of interleukin (IL)-6 and expression of a reporter gene that was driven by a minimal promoter containing two NF-Kappa B elements [18].
  • We show that the mitogen-activated protein kinase inhibitors SB203580 and PD98059 or U0126, as well as a potent mitogen- and stress- activated protein kinase-1 (MSK1) inhibitor H89, counteract tumor necrosis factor (TNF)-mediated stimulation of p65 transactivation capacity [19].
  • Interestingly, TNF-induced cytotoxicity was not affected by SB203580, indicating that p38 MAP kinase might be an interesting target to interfere selectively with TNF-induced gene activation [18].

Anatomical context of Tocris-1202


Associations of Tocris-1202 with other chemical compounds

  • PD98059, but not SB203580, reversed the inhibitory effect of GH on chloride secretion [24].
  • Unlike SAPK2a and SAPK2b, SAPK4 and SAPK3 were not inhibited by the drugs SB 203580 and SB 202190 [25].
  • The LPS-induced stabilization of MIP-2 mRNA and production of MIP-2 protein were abolished when macrophages were incubated with SB 203580 plus PD 184352 (which inhibits the classical MAP kinase cascade) [22].
  • Selective pharmacologic inhibition of p38 MAPK activity with the pyridinyl imidazole drug SB203580 severely impaired the development of mature CD4(+) and CD8(+) single positive (SP) thymocytes from their CD4(+)CD8(+) double positive (DP) precursors in fetal thymic organ culture (FTOC) [26].
  • Both broad-spectrum tyrosine kinase inhibition (genistein) and selective ERK and p38 MAPK inhibition (PD98059 and SB203580, respectively) reduced PE uptake to almost the same extent as CD36 blockade [27].

Gene context of Tocris-1202


Analytical, diagnostic and therapeutic context of Tocris-1202

  • SB203580, a specific inhibitor of p38, was found to inhibit ISGF3 formation but had no apparent effects on signal transducer and activator of transcription (STAT)1 homodimer formation [29].
  • In contrast, administering SB 203580 10 minutes after reperfusion (a time point when maximal MAPK activation had already been achieved) failed to convey significant cardioprotection [2].
  • Immobilization of a suitable SB 203580 analogue and thoroughly optimized biochemical conditions for affinity chromatography permitted the dramatic enrichment and identification of several previously unknown protein kinase targets of SB 203580 [32].
  • The role of p38 and extracellular signal-regulated protein kinase mitogen-activated protein kinase (MAPK) pathways were investigated using the inhibitors SB 203580 and U0 126 and Western blot analysis [33].
  • Flow cytometry revealed that paclitaxel-induced apoptosis of MCF-7 cells and of other paclitaxel-sensitive breast cancer cell lines was maintained in the presence of inhibitors of p38 (SB203580) or mitogen-activated protein/ERK kinase 1 signaling (PD98059) but abrogated when cells were treated with the JNK1/2 inhibitor SP600125 [34].


  1. SAPK2/p38-dependent F-actin reorganization regulates early membrane blebbing during stress-induced apoptosis. Huot, J., Houle, F., Rousseau, S., Deschesnes, R.G., Shah, G.M., Landry, J. J. Cell Biol. (1998) [Pubmed]
  2. Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion. Ma, X.L., Kumar, S., Gao, F., Louden, C.S., Lopez, B.L., Christopher, T.A., Wang, C., Lee, J.C., Feuerstein, G.Z., Yue, T.L. Circulation (1999) [Pubmed]
  3. Expression of the type 2 receptor for cysteinyl leukotrienes (CysLT2R) by human mast cells: Functional distinction from CysLT1R. Mellor, E.A., Frank, N., Soler, D., Hodge, M.R., Lora, J.M., Austen, K.F., Boyce, J.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. mda-7 (IL-24) Mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK. Sarkar, D., Su, Z.Z., Lebedeva, I.V., Sauane, M., Gopalkrishnan, R.V., Valerie, K., Dent, P., Fisher, P.B. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  5. Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy. Elenitoba-Johnson, K.S., Jenson, S.D., Abbott, R.T., Palais, R.A., Bohling, S.D., Lin, Z., Tripp, S., Shami, P.J., Wang, L.Y., Coupland, R.W., Buckstein, R., Perez-Ordonez, B., Perkins, S.L., Dube, I.D., Lim, M.S. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  6. p38 MAPK mediates cardiovascular and behavioral responses induced by central IL-1 beta and footshock in conscious rats. Zheng, R.M., Zou, C.J., Zhu, S.G. Acta Pharmacol. Sin. (2004) [Pubmed]
  7. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Wang, X.Z., Ron, D. Science (1996) [Pubmed]
  8. p38 MAP kinase modulates liver cell volume through inhibition of membrane Na+ permeability. Feranchak, A.P., Berl, T., Capasso, J., Wojtaszek, P.A., Han, J., Fitz, J.G. J. Clin. Invest. (2001) [Pubmed]
  9. p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. Warny, M., Keates, A.C., Keates, S., Castagliuolo, I., Zacks, J.K., Aboudola, S., Qamar, A., Pothoulakis, C., LaMont, J.T., Kelly, C.P. J. Clin. Invest. (2000) [Pubmed]
  10. Mechanical strain activates BNP gene transcription through a p38/NF-kappaB-dependent mechanism. Liang, F., Gardner, D.G. J. Clin. Invest. (1999) [Pubmed]
  11. Loss of E-cadherin leads to upregulation of NFkappaB activity in malignant melanoma. Kuphal, S., Poser, I., Jobin, C., Hellerbrand, C., Bosserhoff, A.K. Oncogene (2004) [Pubmed]
  12. Inhibition of p38 mitogen activated protein kinase controls airway inflammation in cystic fibrosis. Raia, V., Maiuri, L., Ciacci, C., Ricciardelli, I., Vacca, L., Auricchio, S., Cimmino, M., Cavaliere, M., Nardone, M., Cesaro, A., Malcolm, J., Quaratino, S., Londei, M. Thorax (2005) [Pubmed]
  13. 12-lipoxygenase metabolite 12(S)-HETE stimulates human pancreatic cancer cell proliferation via protein tyrosine phosphorylation and ERK activation. Ding, X.Z., Tong, W.G., Adrian, T.E. Int. J. Cancer (2001) [Pubmed]
  14. The relative order of mK(ATP) channels, free radicals and p38 MAPK in preconditioning's protective pathway in rat heart. Yue, Y., Qin, Q., Cohen, M.V., Downey, J.M., Critz, S.D. Cardiovasc. Res. (2002) [Pubmed]
  15. Adenosine-induced late preconditioning in mouse hearts: role of p38 MAP kinase and mitochondrial K(ATP) channels. Zhao, T.C., Hines, D.S., Kukreja, R.C. Am. J. Physiol. Heart Circ. Physiol. (2001) [Pubmed]
  16. Hypertonicity regulates the function of human neutrophils by modulating chemoattractant receptor signaling and activating mitogen-activated protein kinase p38. Junger, W.G., Hoyt, D.B., Davis, R.E., Herdon-Remelius, C., Namiki, S., Junger, H., Loomis, W., Altman, A. J. Clin. Invest. (1998) [Pubmed]
  17. p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons. Ghatan, S., Larner, S., Kinoshita, Y., Hetman, M., Patel, L., Xia, Z., Youle, R.J., Morrison, R.S. J. Cell Biol. (2000) [Pubmed]
  18. The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor. Beyaert, R., Cuenda, A., Vanden Berghe, W., Plaisance, S., Lee, J.C., Haegeman, G., Cohen, P., Fiers, W. EMBO J. (1996) [Pubmed]
  19. Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). Vermeulen, L., De Wilde, G., Van Damme, P., Vanden Berghe, W., Haegeman, G. EMBO J. (2003) [Pubmed]
  20. Involvement of p38MAPK in the regulation of proteolysis by liver cell hydration. Häussinger, D., Schliess, F., Dombrowski, F., Vom Dahl, S. Gastroenterology (1999) [Pubmed]
  21. Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha. Cheung, P.C., Campbell, D.G., Nebreda, A.R., Cohen, P. EMBO J. (2003) [Pubmed]
  22. Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs. Rousseau, S., Morrice, N., Peggie, M., Campbell, D.G., Gaestel, M., Cohen, P. EMBO J. (2002) [Pubmed]
  23. Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2. Ben-Levy, R., Leighton, I.A., Doza, Y.N., Attwood, P., Morrice, N., Marshall, C.J., Cohen, P. EMBO J. (1995) [Pubmed]
  24. Growth hormone reduces chloride secretion in human colonic epithelial cells via EGF receptor and extracellular regulated kinase. Chow, J.Y., Carlstrom, K., Barrett, K.E. Gastroenterology (2003) [Pubmed]
  25. Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. Goedert, M., Cuenda, A., Craxton, M., Jakes, R., Cohen, P. EMBO J. (1997) [Pubmed]
  26. Thymocyte development past the CD4(+)CD8(+) stage requires an active p38 mitogen-activated protein kinase. Fernández, E. Blood (2000) [Pubmed]
  27. Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance. McGilvray, I.D., Serghides, L., Kapus, A., Rotstein, O.D., Kain, K.C. Blood (2000) [Pubmed]
  28. Clostridium difficile toxin A-induced colonocyte apoptosis involves p53-dependent p21(WAF1/CIP1) induction via p38 mitogen-activated protein kinase. Kim, H., Kokkotou, E., Na, X., Rhee, S.H., Moyer, M.P., Pothoulakis, C., Lamont, J.T. Gastroenterology (2005) [Pubmed]
  29. p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons. Goh, K.C., Haque, S.J., Williams, B.R. EMBO J. (1999) [Pubmed]
  30. Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). Cuenda, A., Cohen, P., Buée-Scherrer, V., Goedert, M. EMBO J. (1997) [Pubmed]
  31. Conditional expression of mitogen-activated protein kinase phosphatase-1, MKP-1, is cytoprotective against UV-induced apoptosis. Franklin, C.C., Srikanth, S., Kraft, A.S. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  32. An efficient proteomics method to identify the cellular targets of protein kinase inhibitors. Godl, K., Wissing, J., Kurtenbach, A., Habenberger, P., Blencke, S., Gutbrod, H., Salassidis, K., Stein-Gerlach, M., Missio, A., Cotten, M., Daub, H. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  33. Tauroursodeoxycholic acid protects rat hepatocytes from bile acid-induced apoptosis via activation of survival pathways. Schoemaker, M.H., Conde de la Rosa, L., Buist-Homan, M., Vrenken, T.E., Havinga, R., Poelstra, K., Haisma, H.J., Jansen, P.L., Moshage, H. Hepatology (2004) [Pubmed]
  34. Paclitaxel-induced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt. Sunters, A., Madureira, P.A., Pomeranz, K.M., Aubert, M., Brosens, J.J., Cook, S.J., Burgering, B.M., Coombes, R.C., Lam, E.W. Cancer Res. (2006) [Pubmed]
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