P38 kinases

Not surprisingly, based on the bioactivity of diaryl furans discussed in section 4.2.4.1, triaryl furans have also been investigated as enzyme inhibitors. De Laszlo prepared several 2,3,5-triarylfurans via the Paal-Knorr reactions (for example 44 to 45) and tested these compounds for their activity toward P38 kinase. ... 

The cyclization with a,p-unsaturated nitriles has proven effective for the synthesis of 3-aminothiophene 14, a key intermediate for the synthesis of p38 kinase inhibitors."... 

The most extensive development of pharmacological inhibitors of MAPK cascades members has been for p38 (Table 1) [3]. Small-molecule inhibitors have been developed for two p38 isoforms (a and (3). Pyridinyl imidazole compounds have been known to block inflammation since the early 1970s. Structural analyses have revealed that p38 kinase inhibitors binds to the ATP-binding pocket of p38 thereby acting as competitive inhibitors. The p38 kinase inhibitor SB202190 is able to bind both the low-activity nonphosphorylated... 

A third group of MAPKs are p38 kinases, of which there are four subtypes a, [3, y, and 8. P38 MAPKs are activated by many stimuli including hormones, ligands for G-protein-coupled receptors and stresses [13,17]. P38 MAPK has been implicated in the pathological changes accompanying inflammatory and apoptotic processes of various cell types, including neurons [17] (see Ch. 35 for... 

Bulavin, D. V. et al., Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase, Nature 411, 102-107, 2001. 

Brenner, B., Koppenhoefer, U., Weinstock, C., Linderkamp, O., Lang, F. and Gulbins, E., 1997, Fas- or ceramide-induced apoptosis is mediated by a Rad-regulated activation of Jun N-terminalkinase/p38 kinases and GADD153./. Biol. Chem. 272 22173-22181... 

Fig. 6. Role of signal transduction pathways in phosphorylating H3 at Ser-10 and Ser-28. The Ras-MAPK (mitogen activated protein kinase) pathway is activated by EGF (epidermal growth factor) and TPA (12-0-tetradecanoylphorbol-13-acetate). UV-B activates both the Ras-MAPK pathway and the p38 kinase pathway (for more information about the signal transduction pathways see http // kinase, oci.utoronto.ca/signallingmap.html).

SBDD then guided design of a picomolar p38 kinase inhibitor based on binding to this site, BIRB 796 (5). 

Huang, C., Ma, W. Y.,Ryan, C. A., Dong,Z. (1997). Proteinase inhibitors I and II from potatoes speeifieally bloek UV-indueed activator protein-1 activation through a pathway that is independent of extracellular signal-regulated kinases, c-Jun N-terminal kinases, and P38 kinase. Proc. Natl. Acad. Sci. U. S. A., 94, 11957-11962. 

Raf kinase lead IC50 = 17000 nM, raf kinase IC50 = 290 nM, p38 kinase... 

Fig. 3.5 The p38 kinase signaling pathway inflammatory cytokines, osmotic stress and endotoxins activate this signaling pathway. The maximum activation of p38 requires two M AP2Ks, MKK3 and MKK6. Following activation, p38 translocates to the nucleus and phosphorylates ATF2, ELK1 and MEF-2C. p38 can also be activated independent of MAP2Ks by TAKl-binding protein via TAB1...

Parallel to our group, a few other researchers also performed significant studies on anticancer (3-lactams. For example, (3-lactam derivatives (Fig. 2) induced DNA damage, inhibited DNA replication, and activated the apoptotic death program in human leukemic Jurkat T cells in a time and concentration-dependent manner. Importantly, (3-lactam 69 also inhibited proliferation and induced apoptosis in other human solid tumor cell lines (breast, prostate, and head-and-neck). It was believed that induction of apoptosis by 69 is associated with activation of p38 mitogen-activated protein (MAP) kinase, release of mitochondrial cytochrome c, and activation of the caspases. It was reported that apoptosis is blocked by a specific inhibitor to p38 kinase, implicating p38 MAP kinase as the major factor in (3-lactam-induced apoptosis [154]. This study was very significant. 

She QB, Bode AM, Ma WY, Chen NY, Dong Z. 2001. Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. Cancer Res 61 1604-1610. 

Ku, N. O., Azhar, S., and Omary, M. B. (2002a). Keratin 8 phosphorylation by p38 kinase regulates cellular keratin filament reorganization Modulation by a keratin 1-like disease causing mutation. / Biol. Chem. 277, 10775-10782. 

Bl. Badger, A. M., Bradbeer, J. N., Votta, B., Lee, J. C., Adams, J. L., and Griswold, D. E., 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 (1996). 

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