Intriguingly, it has been reported that activated MEK1 but not MEK2 induces epidermal hyperplasia in transgenic mice. RNA interference and gene invalidation studies have also suggested that MEK1 and MEK2 may contribute differentially to tumorigenesis. The physiopathological relevance of these observations to human cancer remains unclear. Second, it helps understand why the first-generation MEK1/2 inhibitors PD98059, U0126 and PD184352 were also found to inhibit MEK5 and the ERK5 MAP kinase pathway at higher concentrations. Elucidation of the crystalstructures. of MEK1 and MEK2 has revealed that MEK5 share 83% amino acid identity with MEK1 in the PD184352-like inhibitor-binding pocket. These MEK1/2 inhibitors have been used in thousands of papers and have proven extremely useful tools to investigate the biological functions of the ERK1/2 MAP kinase pathway. However, their inhibitory activity towards MEK5, albeit weaker, indicates that we should be cautious in the interpretation of data obtained at high concentrations of inhibitor.
Frémin C, Meloche S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy[J]. Journal of hematology & oncology, 2010, 3(1): 1.