Putative allosteric MEK1 and MEK2 inhibitors

Background: Over the last decade, the pharmaceutical industry has invested significantly in efforts to identify novel inhibitors of the mitogen-activated protein kinases MEK1 and MEK2. Unsurprisingly, several ATP-competitive inhibitors have been identified, but the discovery of allosteric inhibitors has been the main focus for the development of novel therapies. A number of allosteric MEK1 and MEK2 inhibitors have been reported to exhibit exquisite selectivity when profiled against large panels of kinases. Of the eight MEK inhibitors that have entered the clinic, it is believed that the majority, if not all, bind allosterically. Objective: This review focuses on the patenting activity concerning putative allosteric MEK inhibitors, and their progression into the clinic. Method: An analysis of the putative allosteric MEK inhibitor patent estate from the first-use application for PD-098059 in 1996 through to February 2008 was undertaken. An evaluation and summary of such therapies that have entered the clinic are provided. Conclusion: The overwhelming majority of patents filed that describe putative allosteric MEK inhibitors are based on a diarylamine scaffold. The ubiquitous expression of MEK throughout the body, and its central role in the cell signalling pathway, will undoubtedly ensure that inhibitors continue to be progressed into the clinic over the next decade.