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, 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. 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
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