ERK pathway

ARRY-438162 is a recently disclosed potent and selective ATP non-competitive MEK1/2 inhibitor that is in Phase lb clinical trials as an anti-arthritic agent [24]. ARRY-438162 inhibited the MEK1/2 enzyme with an IC50 = 12 nM and pERK in cells with an IC50 = 11 nM. ATP non-competitive inhibition may be responsible for equipotent inhibition of MEK1/2 in vitro and pERK in cells. The compound was selective against a panel of 220 other kinases. 

ARRY-438162 was found to be efficacious in a number of animal models of inflammation. For example, in a collagen-induced arthritis model in rats, oral administration of ARRY-438162 at lOmg/kg q.d. significantly inhibited paw swelling which was accompanied by inhibition of cartilage damage in the joint and 80% inhibition of pERK in the tissue from the foot with induced arthritis. 

In a Phase la study in healthy volunteers, ARRY-438162 was well tolerated up to 20mg/kg q.d. oral dose. There was a dose proportional increase in plasma concentration and decrease in the production of IL-1 ft, TNFa, IL-6 and pERK in the ex-vivo-stimulated whole blood from drug treated volunteers. Array has initiated a Phase lb study of ARRY-438162 in combination with methotrexate in rheumatoid arthritis patients with the goals of assessing safety, tolerability, pharmacokinetics (PK), biomarkers and initial signs of efficacy. 

ARRY-142886 (AZD6244) is another potent, selective and ATP non-competitive MEK1/2 inhibitor with IC50 = 12 nM. This compound inhibited cellular pERK with an ICYn 10 nM and tumor growth in a number of xenograft models and is reported to be in Phase II clinical trials in cancer patients [25]. 

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Figure 7.1 Major signaling pathways relevant to this chapter. Simplified schematic diagram of the major signaling pathways which impinge on mRNA translation I. The phosphatidylinositide 3-kinase (PI 3-kinase) pathway II/III. MAP kinases, especially the classical MAP kinase (ERK) pathway and the p38 MAP kinase pathway IV. The mammalian target of rapamycin (mTOR) pathway. Strictly, this diagram shows the rapamycin-sensitive events linked to mTORCl. Selected inhibitors and their sites of action are shown. A numberof components and cross-connections have been omitted for clarity.

PD098059 PD184352 MEK1/2 (ERK pathway) MEK1/2 (ERK pathway) (Alessi et al., 1995 Dudley et al, 1995) (Davies et al., 2000) Also inhibits MEK5 (Kamakura et al., 1999) and activates AMPK (Dokladda et al., 2005)... 

Figure 7.2 Organization of specific signaling modules. (A) The arrangement of upstream and downstream kinases in a typical MAP kinase module is shown, the named examples being from the classical MAP kinase (ERK) pathway. (B) The known composition of mTORCl and mTORC2 is shown.

Krapivinsky, G., Krapivinsky, L., Manasian, Y. et al. The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRFl. Neuron 40 775-784, 2003. 

Multiple interactions are also being demonstrated between the traditional second-messenger pathways and the MAPK cascades. Free (3y G protein subunits, generated upon activation of receptors coupled to the G family, lead to activation of the ERK pathway. The mechanism by which this occurs, which may involve an interaction between the subunits and Ras or Raf, is a subject of intensive research (see Ch. 19). In addition, increases in cellular Ca2+ concentrations lead to stimulation of the ERK pathway, apparently via phosphorylation by CaMKs of proteins, for example She and Grb, that link growth factor receptor tyrosine kinases to Ras. Activation of the... 

Miglaccio A, Piccolo D, Castoria G, DiDomenico M, Bilancio A, Lombardi M, Gong W, Beato M, Auricchio F (1998) Activation of the Src/p21(ras)/Erk pathway by progesterone receptor via cross-talk with estrogen receptor. EMBO J 17 2008... 

A further susceptible point for insulin-regulated signaling pathways is the ribosomal protein S6. Under the influence of insulin, S6 is phosphorylated by a specific protein kinase, the p70 kinase, resulting in increased levels of translation of certain mRNAs. Several pathways including the MAPK/ERK pathway (see chapter 10) and the Akt kinase pathway can contribute to the activation of the p70 kinase. 

Fig. 10.2. Components and activation of the ERK pathway. Ordering and specificity of protein kinases in the ERK pathway. ExtraceUular signals are registered via receptor tyrosine kinases and passed on to the Ras protein. Ras GTP activates protein kinases belonging to the group of MAPKK kinases (Raf kinases and MEEKs). The MAPKK kinases phosphorylate the downstream group of protein kinases, the MAPKKs at two Ser residues. The MAPKKs phosphorylate the MAPKs (ERKl and ERK2) at a Tyr and a Thr residue, and thus are classified as dual specificity kinases. MAPK mitogenic activated protein kinase ERK extracellularly regulated kinase MEK MAP/ERK kinase MAPKK MAPK kinase MAPKKK MAPKK kinase MEKK MEK kinase.

The substrates of the MAP kinase pathway are very diverse and include both cytosolic and nuclear localized proteins. Phospholipase A2 and transcription factors of the Ets family are well characterized substrates of the ERK pathway. Phosphorylation of a Ser residue of phospholipase A2 by ERK proteins leads to activation of the lipase activity. Consequently, there is an increase in release of arachidonic acid and of lyso-phospholipids, which can act immediately as diffusible signal molecules or may represent first stages in the formation of second messenger molecules. 

Fung MK, Cheung HW, Ling MT et al. Role of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumour cells. Br J Cancer 2006 95 475 84. 

Crosstalk between the PI3K and the Raf/MEK/ERK pathways has been reported on multiple levels, with some research stating that PI3K activity is essential for induction of Raf/MEK/ERK activity (Vivanco and Sawyers 2002 Sebolt-Leopold and... 

Rommel C, Clarke BA, Zimmermann S, Nunez L, Rossman R, Reid K, Moelling K, Yancopoulos GD, Glass DJ (1999) Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. Science 286(5445) 1738-1741... 

This results in induction of the sos-ras-MEK-ERK pathway. The ERK pathway has also been implicated in thymocyte selection and maturation, TH2 differentiation, and IL-4-induced STAT6 and IL-4 receptor phosphorylation. 

Chang F, Steelman LS, Lee JT, Shelton JG, et al. 2003. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokines to transcription factors potential targeting for therapeutic intervention. Leukemia. 17 1263-1293. 

Lopez-Pedrera, C., Buendia, P., Cuadrado, MJ., Siendones, E., Aguirre, M.A., Barbarroja, N., Montiel-Duarte, C., Torres, A., Khamashta, M., and F. Velasco, 2006, Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF-kappaB/Rel proteins via the p38 mitogen-activated protein kinase pathway, and of the MEK-l/ERK pathway.Arthritis Rheum. 54(1) 301—11. 

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