Mitogen-activated protein kinase kinase (also known as MAP2K, MEK, MAPKK) is a kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).
In eukaryotic cell types, the ability to recognize and respond to extracellular stimuli is coordinated by specified intracellular signaling programs that culminate in the activation of mitogen activate protein kinases (MAPKs). These MAPKs coordinately regulate a diversity of cellular processes, including gene expression, cell division, motility, differentiation, metabolism, survival and apoptosis.
These pathways interpret the resultant outcome in the context of the current biological milieu. The signaling sequence typically originates upon ligand binding or in response to extracellular stress. The subsequent events in the MAPK signaling pathway are unique and conserved since it involves a series of phosphorylation events activating the downstream kinases of the cascade; MEKK (mitogen-activated kinase kinase kinase) phosphorylates MEK (mitogen-activated kinase kinase), which in turn phosphorylates another kinase, ERK (extracellular signal-regulated kinase). ERKs exhibit multiple phosphorylation states responsible for their subcellular localization and enactment of specific responses such as cell growth, proliferation, survival, and development.
The flavone PD 098059 is a known MEK-1/2 and 5 inhibitor. The first MEK-1 and MEK-2 inhibitor, PD98059 was identified in an in vitro screen for inhibitors of ERK activation. It also shows inhibitory activity against MEK-5. Some studies have shown PD98059 to be a non-competitive inhibitor of ATP, while others have shown it to be involved in activation of a cAMP-activated protein kinase mechanism.
UO126 binds selectively to MEK-1 and MEK-2 with IC50 of 0.07±0.02 µM and 0.06±0.02 µM respectively. It exhibits non-competitive inhibition with respect to ATP or ERK, thus it might bind to an allosteric site on MEK.
An x-ray crystal structure, 1S9J, of the diphenylamine MEK-1/2 inhibitor PD318088 bound to MEK-1 is known. CI-1040 was designed as a MEK-1/2 inhibitor for treatment of cancer. It was the first MEK inhibitor that progressed into clinical trials. SAR were explored for the diphenylamine scaffold.
Specific MEK-5 inhibitors were reported by Boehringer Ingelheim, discovered through high throughput screening. BIX02188 and BIX02189 showed inhibition of MEK-5 catalytic activity in dose dependent manner with an IC50 4.3 and 1.5 nM, respectively.
Other classes of MEK inhibitors
Other chemical classes are also being explored as MEK inhibitors, such as coumarinbased compounds (G8935, G0328), pyrrolopyridazines, and imido-substituted 2-chloro-1,4-naphthoquinones.
Inhibition of MEK-5 might have potential as an anti-cancer target. Yet, only a single selective MEK-5 inhibitor has been identified, BIX02189, an indolinone-6-carboxamide. The development of new scaffolds and new inhibitors should permit a better characterization of the functional role of the enzyme both in vitro and in vivo.
Ishveen Kaur Chopra. DESIGN AND SYNTHESIS OF CDK-5 AND MEK-5 INHIBITORS AND SYNTHESIS TOWARDS TUBULYSIN ANALOGS