Developments in mitogen-induced extracellular kinase 1 inhibitors and their use in the treatment of disease

Multiple signal transduction pathways converge on the Raf-mitogen-induced extracellular kinase (MEK)-extracellular signal-regulated kinase (Erk) cascade to effect diverse cellular processes, including proliferation, differentiation, survival, apoptosis and organ functions such as memory consolidation. Improper activation of this pathway contributes significantly to numerous diseases, including cancer and various immune disorders. Specific inhibition of this signalling cascade thus offers great therapeutic potential for many diseases. Since the discovery of the first MEK1 inhibitor in 1995, several novel classes of inhibitors, with varying selectivity for MEK1, have been developed. Clinical applications for some of these have been investigated, with the majority focusing on proliferative diseases in which abnormally increased Erk activity plays a major role, most notably cancer, or immunological and inflammatory conditions such as arthritis and organ transplant rejection. To a lesser extent, ischaemia/reperfusion (I/R) injury and chronic pain disorders have also been targeted.