p38 MAP kinase is a ubiquitous, highly conserved enzyme which regulates the production of proinflammatory mediators (such as TNFα and IL-1) in response to inflammatory cytokines or environmental stress [6,12-13]. Four p38 MAP kinase homologs have been identified, as have the upstream and downstream signalling mechanisms and enzyme substrates [5,8,15]. Inhibition of these enzymes reduces inflammatory cytokine synthesis. p38 MAP kinase enzymes are therefore highly pursued drug targets for conditions including inflammation, arthritis and other joint diseases, septic shock, and myocardial injury.

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3. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

4. Eyers PA, Craxton M, Morrice N, Cohen P, Goedert M. (1998) Conversion of SB 203580-insensitive MAP kinase family members to drug-sensitive forms by a single amino-acid substitution. Chem Biol, 5 (6): 321-8. [PMID:9653550]

5. Han J, Jiang Y, Li Z, Kravchenko VV, Ulevitch RJ. (1997) Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature, 386 (6622): 296-9. [PMID:9069290]

6. Han J, Lee JD, Bibbs L, Ulevitch RJ. (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science, 265 (5173): 808-11. [PMID:7914033]

7. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT et al.. (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol, 26 (1): 127-32. [PMID:18183025]

8. Lee JC, Kumar S, Griswold DE, Underwood DC, Votta BJ, Adams JL. (2000) Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology, 47 (2-3): 185-201. [PMID:10878289]

9. Mader M, de Dios A, Shih C, Bonjouklian R, Li T, White W, López de Uralde B, Sánchez-Martinez C, del Prado M, Jaramillo C et al.. (2008) Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38alpha MAP kinase inhibitors with excellent in vivo antiinflammatory properties. Bioorg Med Chem Lett, 18 (1): 179-83. [PMID:18039577]

10. Millan DS, Bunnage ME, Burrows JL, Butcher KJ, Dodd PG, Evans TJ, Fairman DA, Hughes SJ, Kilty IC, Lemaitre A et al.. (2011) Design and synthesis of inhaled p38 inhibitors for the treatment of chronic obstructive pulmonary disease. J Med Chem, 54 (22): 7797-814. [PMID:21888439]

11. Moffett K, Konteatis Z, Nguyen D, Shetty R, Ludington J, Fujimoto T, Lee KJ, Chai X, Namboodiri H, Karpusas M et al.. (2011) Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD). Bioorg Med Chem Lett, 21 (23): 7155-65. [PMID:22014550]

12. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev, 22 (2): 153-83. [PMID:11294822]

13. Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ. (1995) Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem, 270 (13): 7420-6. [PMID:7535770]

14. Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB. (2007) p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell, 11 (2): 175-89. [PMID:17292828]

15. Wang XZ, Ron D. (1996) Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science, 272 (5266): 1347-9. [PMID:8650547]