A potent inhibitor of MEK1/2
IC50: 8 nM for MEK [1]
PD 198306 is a potent, selective and non-ATP competitive MAPK/ERK-kinase (MEK) inhibitor. MEK is a kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).
In vitro: PD 198306 inhibits the isolated MEK at a concentration of 8 nM and inhibits MEK activity in synovial fibroblasts at 30–100 nM, depending on the species. PD 198306 is highly selective for MEK and has a IC50 of >4 uM for c-Src, >1 uM for ERK, >4 uM for cyclin-dependent kinases and >10 uM for phosphatidylinositol 3-kinase [1].
In vivo: Rabbits treated with PD 198306 showd a significant dose-dependent reduction in the level of phospho-ERK-1/2 and a lower level of MMP-1. PD 198306 can partially decrease the development of some of the structural changes in experimental rabbit model of osteoarthritis [1]. PD 198306 dose-dependently blocked static allodynia in both the streptozocin and the chronic constriction injury models of neuropathic pain. These antihyperalgesic effects correlated with a reduction in the elevated levels of active ERK1 and 2 in lumbar spinal cord [2].
Clinical trial: So far, no clinical study has been conducted.
参考文献:
[1] Pelletier JP, Fernandes JC, Brunet J, Moldovan F, Schrier D, Flory C, Martel-Pelletier J.? In vivo selective inhibition of mitogen-activated protein kinase kinase 1/2 in rabbit experimental osteoarthritis is associated with a reduction in the development of structural changes. Arthritis Rheum. 2003 Jun;48(6):1582-93.
[2] Ciruela A, Dixon AK, Bramwell S, Gonzalez MI, Pinnock RD, Lee K.? Identification of MEK1 as a novel target for the treatment of neuropathic pain. Br J Pharmacol. 2003 Mar;138(5):751-6.
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