Project 461610

The development of selective chemical inhibitors of protein kinases is of key importance for understanding kinase mechanisms and exploring their roles in physiology and disease. These chemical tools are also essential to validate potential drug targets and to spur the development of new medicines. Protein kinases are considered highly druggable given the extensive know-how and successful record in kinase drug discovery. MAP kinases are a subfamily of protein kinases that play important roles in the control of cell proliferation, differentiation and immune response. These enzymes have attracted considerable attention as their aberrant regulation has been linked to several human diseases including many cancers. Our laboratory has recently unveiled novel roles of the MAP kinases ERK3 and ERK4 in the pathogenesis of cancer. However, no chemical inhibitor of ERK3 or ERK4 has been available, which hampers the study of their functions and their validation as potential drug targets. In an effort to identify novel chemical inhibitors of ERK3/ERK4, we have recently screened a collection of small molecules and identified a series of compounds that potently inhibit ERK3 and ERK4 kinase activity. This project aims to improve the potency and pharmaceutical properties of the molecules and test their activity in preclinical models of cancer. Our proposal has the potential to lead to the identification of first-in-class dual ERK3/ERK4 inhibitors for cancer therapy.