Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: Preclinical analysis of efficacy and selectivity

Journal of Pharmacology and Experimental Therapeutics

Volumn 327, Issue 3, 2008, Pages 610-619

  Hill, Ronald J ^a   Dabbagh, Karim ^a   Phippard, Deborah ^a   Li, Ching ^b   Suttmann, Rebecca T ^a   Welch, Mary ^a   Papp, Eva ^a   Song, Kyung W ^a   Chang, Kung Ching ^a   Leaffer, David ^a   Kim, Yong Nam ^a   Roberts, Richard T ^a   Zabka, Tanja S ^a   Aud, Dee ^a   Dal Porto, Joseph ^a   Manning, Anthony M ^a,c   Peng, Stanford L ^a   Goldstein, David M ^a   Wong, Brian R ^a  

^a ROCHE BIOSCIENCE   (United States)

^b IMPERIAL COLLEGE LONDON   (United Kingdom)

^c BIOGEN   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HEAT SHOCK PROTEIN 27; INTERLEUKIN 1BETA; INTERLEUKIN 6; MITOGEN ACTIVATED PROTEIN KINASE 11; MITOGEN ACTIVATED PROTEIN KINASE 14; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; PAMAPIMOD; PROTEIN C JUN; R 9111; STRESS ACTIVATED PROTEIN KINASE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ARTICLE; AUTOIMMUNE DISEASE; CONTROLLED STUDY; CYTOKINE PRODUCTION; CYTOKINE RELEASE; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENCY; DRUG SELECTIVITY; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME SPECIFICITY; EXPERIMENTAL MODEL; FEMALE; HUMAN; HUMAN CELL; HUMAN TISSUE; HYPERALGESIA; IC 50; MALE; MINIPUMP; MONOCYTE; MOUSE; NONHUMAN; OSTEOLYSIS; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RAT; RHEUMATOID ARTHRITIS; SYSTEMIC LUPUS ERYTHEMATOSUS;

ANIMALS; ARTHRITIS, RHEUMATOID; DRUG EVALUATION, PRECLINICAL; HUMANS; INFLAMMATION; INHIBITORY CONCENTRATION 50; INTERLEUKIN-1BETA; INTERLEUKIN-6; KIDNEY DISEASES; MICE; MONOCYTES; OSTEOPOROSIS; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PROTEIN ISOFORMS; PROTEIN KINASE INHIBITORS; PYRIDONES; PYRIMIDINES; SYNOVIAL FLUID; TREATMENT OUTCOME; TUMOR NECROSIS FACTOR-ALPHA;

EID: 57349130600     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.108.139006     Document Type: Article

References (40)

1. Adams RH, Porras A, Alonso G, Jones M, Vintersten K, Panelli S, Valladares A, Perez L, Klein R, and Nebreda AR (2000) Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. Mol Cell 6:109-116.
2. Allen M, Svensson L, Roach M, Hambor J, McNeish J, and Gabel CA (2000) Deficiency of the stress kinase p38alpha results in embryonic lethality: characterization of the kinase dependence of stress responses of enzyme-deficient embryonic stem cells. J Exp Med 191:859-870.
3. Alonso G, Ambrosino C, Jones M, and Nebreda AR (2000) Differential activation of p38 mitogen-activated protein kinase isoforms depending on signal strength. J Biol Chem 275:40641-40648.
4. Badger AM, Bradbeer JN, Votta B, Lee JC, Adams JL, and Griswold DE (1996) Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. J Pharmacol Exp Ther 279:1453-1461.
5. Beardmore VA, Hinton HJ, Eftychi C, Apostolaki M, Armaka M, Darragh J, McIlrath J, Carr JM, Armit LJ, Clacher C, et al. (2005) Generation and characterization of p38beta (MAPK11) gene-targeted mice. Mol Cell Biol 25:10454-10464.
6. Brook M, Sully G, Clark AR, and Saklatvala J (2000) Regulation of tumour necrosis factor alpha mRNA stability by the mitogen-activated protein kinase p38 signalling cascade. FEBS Lett 483:57-61.
7. Campbell J, Ciesielski CJ, Hunt AE, Horwood NJ, Beech JT, Hayes LA, Denys A, Feldmann M, Brennan FM, and Foxwell BM (2004) A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis. J Immunol 173:6928-6937.
8. Chen Z, Gibson TB, Robinson F, Silvestro L, Pearson G, Xu B, Wright A, Vanderbilt C, and Cobb MH (2001) MAP kinases. Chem Rev 101:2449-2476.
9. Cohen P (1997) The search for physiological substrates of MAP and SAP kinases in mammalian cells. Trends Cell Biol 7:353-361.
10. Cohen SB, Cheng T, Chindalore V, Damjanov N, Burgos-Vargas R, DeLora P, Zimany K, Travers H, and Caulfield JP (2008) Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study in patients with active rheumatoid arthritis. Arthritis Rheum, in press.
11. Court NW, dos Remedios CG, Cordell J, and Bogoyevitch MA (2002) Cardiac expression and subcellular localization of the p38 mitogen-activated protein kinase member, stress-activated protein kinase-3 (SAPK3). J Mol Cell Cardiol 34:413-426.
12. Dean JL, Sully G, Clark AR, and Saklatvala J (2004) The involvement of AU-rich element-binding proteins in p38 mitogen-activated protein kinase pathway-mediated mRNA stabilisation. Cell Signal 16:1113-1121.
13. Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, et al. (2005) A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23:329-336.
14. Frevel MA, Bakheet T, Silva AM, Hissong JG, Khabar KS, and Williams BR (2003) p38 Mitogen-activated protein kinase-dependent and -independent signaling of mRNA stability of AU-rich element-containing transcripts. Mol Cell Biol 23:425-436.
15. Ganju P, Davis A, Patel S, Núñez X, and Fox A (2001) p38 stress-activated protein kinase inhibitor reverses bradykinin B(1) receptor-mediated component of inflammatory hyperalgesia. Eur J Pharmacol 421:191-199.
16. Goldstein DM and Gabriel T (2005) Pathway to the clinic: inhibition of P38 MAP kinase: a review of ten chemotypes selected for development. Curr Top Med Chem 5:1017-1029.
17. Hale KK, Trollinger D, Rihanek M, and Manthey CL (1999) Differential expression and activation of p38 mitogen-activated protein kinase alpha, beta, gamma, and delta in inflammatory cell lineages. J Immunol 162:4246-4252.
18. Han J, Jiang Y, Li Z, Kravchenko VV, and Ulevitch RJ (1997) Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature 386:296-299.
19. Inoue T, Boyle DL, Corr M, Hammaker D, Davis RJ, Flavell RA, and Firestein GS (2006) Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis. Proc Natl Acad Sci U S A 103:5484-5489.
20. Iwata Y, Wada T, Furuichi K, Sakai N, Matsushima K, Yokoyama H, and Kobayashi K (2003) p38 Mitogen-activated protein kinase contributes to autoimmune renal injury in MRL-Fas lpr mice. J Am Soc Nephrol 14:57-67.
21. Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, and Zhang YQ (2007) Protein kinases as potential targets for the treatment of pathological pain. Handb Exp Pharmacol 177:359-389.
22. Karin M (2005) Inflammation-activated protein kinases as targets for drug development. Proc Am Thorac Soc 2:386-390; discussion 394-395.
23. Kumar S, Boehm J, and Lee JC (2003) p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2:717-726.
24. Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, and Landvatter SW (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372:739-746.
25. Li X, Udagawa N, Itoh K, Suda K, Murase Y, Nishihara T, Suda T, and Takahashi N (2002) p38 MAPK-mediated signals are required for inducing osteoclast differentiation but not for osteoclast function. Endocrinology 143:3105-3113.
26. Manning G, Whyte DB, Martinez R, Hunter T, and Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912-1934.
27. Medicherla S, Ma JY, Mangadu R, Jiang Y, Zhao JJ, Almirez R, Kerr I, Stebbins EG, O'Young G, Kapoun AM, et al. (2006) A selective p38 alpha mitogen-activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis. J Pharmacol Exp Ther 318:132-141.
28. Mudgett JS, Ding J, Guh-Siesel L, Chartrain NA, Yang L, Gopal S, and Shen MM (2000) Essential role for p38alpha mitogen-activated protein kinase in placental angiogenesis. Proc Natl Acad Sci U S A 97:10454-10459.
29. Nishikawa M, Myoui A, Tomita T, Takahi K, Nampei A, and Yoshikawa H (2003) Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthritis Rheum 48:2670-2681.
30. Pargellis C and Regan J (2003) Inhibitors of p38 mitogen-activated protein kinase for the treatment of rheumatoid arthritis. Curr Opin Investig Drugs 4:566-571.
31. Saccani S, Pantano S, and Natoli G (2002) p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment. Nat Immunol 3:69-75.
32. Saklatvala J (2004) The p38 MAP kinase pathway as a therapeutic target in inflammatory disease. Curr Opin Pharmacol 4:372-377.
33. Schett G, Redlich K, Xu Q, Bizan P, Gröger M, Tohidast-Akrad M, Kiener H, Smolen J, and Steiner G (1998) Enhanced expression of heat shock protein 70 (hsp70) and heat shock factor 1 (HSF1) activation in rheumatoid arthritis synovial tissue: differential regulation of hsp70 expression and hsf1 activation in synovial fibroblasts by proinflammatory cytokines, shear stress, and antiinflammatory drugs. J Clin Invest 102:302-311.
34. Schieven GL (2005) The biology of p38 kinase: a central role in inflammation. Curr Top Med Chem 5:921-928.
35. Wada Y, Nakajima-Yamada T, Yamada K, Tsuchida J, Yasumoto T, Shimozato T, Aoki K, Kimura T, and Ushiyama S (2005) R-130823, a novel inhibitor of p38 MAPK, ameliorates hyperalgesia and swelling in arthritis models. Eur J Pharmacol 506:285-295.
36. Wesselborg S, Bauer MK, Vogt M, Schmitz ML, and Schulze-Osthoff K (1997) Activation of transcription factor NF-kappaB and p38 mitogen-activated protein kinase is mediated by distinct and separate stress effector pathways. J Biol Chem 272:12422-12429.
37. Westra J and Limburg PC (2006) p38 mitogen-activated protein kinase (MAPK) in rheumatoid arthritis. Mini Rev Med Chem 6:867-874.
38. Winzen R, Kracht M, Ritter B, Wilhelm A, Chen CY, Shyu AB, Müller M, Gaestel M, Resch K, and Holtmann H (1999) The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism. EMBO J 18:4969-4980.
39. Zhang J, Shen B, and Lin A (2007) Novel strategies for inhibition of the p38 MAPK pathway. Trends Pharmacol Sci 28:286-295.
40. Zhu T and Lobie PE (2000) Janus kinase 2-dependent activation of p38 mitogen-activated protein kinase by growth hormone: resultant transcriptional activation of ATF-2 and CHOP, cytoskeletal re-organization and mitogenesis. J Biol Chem 275:2103-2114.