New small-molecule inhibitors of mitogen-activated protein kinase kinase

作者：Spicer Julie A^*

来源：Expert Opinion on Drug Discovery, 2008, 3(7): 801-817.

DOI：10.1517/13543770802109872

• ARRY-142886
• CI-1040
• ERK
• extracellular-signal-regulated kinase
• MAP/ERK kinase
• MAP kinase pathway
• MEK
• MEK inhibitor
• mitogen-activated protein kinase pathway
• PD0325901

Background: Overexpression of the Ras/Raf/MEK/ERK (extracellular-signal-regulated kinase) pathway is associated with the formation, progression and survival of tumours and has also been implicated in a diverse range of therapeutic areas such as arthritis, organ transplant rejection, asthma and developmental disorders. One approach to down regulation of this pathway is through the inhibition of mitogen-activated protein kinase kinase 1/2 (MEK1/2). Objective: The importance of the mitogen-activated protein kinase (MAPK) pathway, MEK1/2 as a therapeutic target and early MEK1/2 inhibitors is discussed, followed by an overview of recent patent activity in the area. Methods: The patent literature was searched for inhibitors of MEK1/2 published within the last three years; these results are described. Other relevant publications that provide further insight into the discovery and development of these compounds are also discussed. Conclusion: The determination of a crystal structure with inhibitor bound has allowed the design of exquisitely selective and potent inhibitors of MEK1/2. Several allosteric inhibitors have advanced to clinical trial and shown some efficacy in cancer as single agents, but the future application of MEK1/2 inhibitors is likely to be either in combination with other therapies or in disorders which are genetically defined as being dependent on the MAPK pathway.

• 出版日期2008-7