Description
PD 198306 is an orally bioavailable and potent inhibitor of MAPK kinase 1/2 (MEK1/2; IC50 = 8 nM). It is selective for MEK1/2 over ERK, c-Src, PI3Kγ, and cyclin-dependent kinases (IC50s = >1 μM). PD 198306 (3-100 μM) reduces ERK1/2 phosphorylation and inhibits growth of HL-60 cells in vitro. In vivo, PD 198306 (10-30 mg/kg) reduces ERK1/2 phosphorylation and matrix metalloproteinase-1 (MMP-1) expression in a dose-dependent manner in a rabbit model of osteoarthritis. It also reduces ERK1/2 activity in the lumbar spinal cord and blocks static allodynia in rat models of neuropathic pain induced by streptozotocin or chronic constriction injury.
Uses
PD 198306 is a cell-permeable and highly selective potent inhibitor of MEK 1/2.
Definition
ChEBI: N-(cyclopropylmethoxy)-3,4,5-trifluoro-2-(4-iodo-2-methylanilino)benzamide is an aminobenzoic acid.
Biological Activity
Potent inhibitor of MEK1/2. Inhibits isolated enzyme at a concentration of 8 nM and inhibits MEK activity in synovial fibroblasts at concentrations of 30-100 nM. Highly selective for MEK; IC 50 values are > 1, > 4, > 4 and > 10 μ M for ERK, c-Src, cdks and PI 3-kinase γ respectively. Antihyperalgesic; blocks static allodynia in the streptozocin model of neuropathic pain following i.t. administration.
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].
References
[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.
