Interference No. 104,436 Paper 98
Shyamala v. Hillman Page 9
Are kinases in general a good target for drug discovery?
Which p38 MAPK isoform(s) play(s) a crucial role in immune and
inflammatory cells?
What role does p38 MAPK play in NF-xB-dependent trariscription?
What role does JNK play during inflammation?
0 Can specific inhibitors be developed to target the p38a isoform without
toxicity?
[63] In view of Herlaar, we find that a s late as 1999 researchers were still trying to elucidate MAPK
pathways, identify relationships between kinases in the padiway, and identify inhibitors for those
kinases, but that the research was still marked by considerable uncertainty.
[64] The Lee article [ 1005] was published in 1999.
[65] Lee confirms that, at least in 1999, p38 MAPK inhibitors were believed to be "efficacious in
several disease models, including inflammation, arthritis and other joint diseases, septic shock,
and myocardial injury" [1005, abstract].
[66] Lee notes the identification of four p38 homologs (a, P, y, and 8) in 1996-97 [1005 at 390:Rl.
[67] Lee further notes that in 1997-1998, the art found that MKK3 selectively activates p38a and
p38y, while MKK6 activates all four p38 isoforms. MKK4 activates p38 and another kinase
[1005 at 390:R].
[68] According to Lee, several substrates had been identified for p38 in vitro, only a few substrates
(and only for p38a) had been identified in vivo [ 1005 at 390:R].
J.C. Lee et al., "p38 Mitogen-Activated Protein Kinase Inhibitors-Mechanisms and Therapeutic Potentials",
82 Pharmacol. Ther. 389 (1999) (Lee). The authors are with SmithKline Beecham Pharmaceuticals.
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