A synthetic inhibitor of the mitogen-activated protein kinase cascade.

TLDR

Treatment of cells with growth factors activates a phosphorylation cascade that triggers mitogen‑activated protein kinases (MAPKs or ERKs). PD 098059 is a selective MEK inhibitor that blocks MAPK activation, suppresses phosphorylation of downstream substrates, inhibits cell proliferation, reverses ras‑transformed phenotypes, and demonstrates that the MAPK pathway is essential for ras‑driven growth. This compound provides an invaluable tool for elucidating the role of the MAPK cascade in diverse biological contexts.

Abstract

Treatment of cells with a variety of growth factors triggers a phosphorylation cascade that leads to activation of mitogen-activated protein kinases (MAPKs, also called extracellular signal-regulated kinases, or ERKs). We have identified a synthetic inhibitor of the MAPK pathway. PD 098059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one] selectively inhibited the MAPK-activating enzyme, MAPK/ERK kinase (MEK), without significant inhibitory activity of MAPK itself. Inhibition of MEK by PD 098059 prevented activation of MAPK and subsequent phosphorylation of MAPK substrates both in vitro and in intact cells. Moreover, PD 098059 inhibited stimulation of cell growth and reversed the phenotype of ras-transformed BALB 3T3 mouse fibroblasts and rat kidney cells. These results indicate that the MAPK pathway is essential for growth and maintenance of the ras-transformed phenotype. Further, PD 098059 is an invaluable tool that will help elucidate the role of the MAPK cascade in a variety of biological settings.