Ubiquitous across most organisms, the mitogen-activated protein kinase (MAPK) pathways are responsible for essential cellular processes such as cell growth, division, and death. Dysregulation of these processes can lead to a myriad of debilitating diseases. Key to the MAPK signaling pathways is the MAPK/ERK (MEK) family of kinases. Of the seven kinases in this family, MEK1 and MEK2 were the first to be discovered and thoroughly studied, giving rise to three FDA-approved MEK1/2 inhibitors as therapies for skin cancer. Additional MEK1/2 inhibitors are also in clinical trials for other indications, but there has been little investigation into the rest of the MEK family to date, despite the high clinical relevance. In particular, high levels of MEK4 (otherwise known as MAP2K4 or MKK4) have been observed in conjunction with cancers such as pancreatic cancers, which has among the lowest survival rates. While the involvement of MEK4 in these diseases is now being more heavily studied, many of the molecular mechanisms remain unknown. In order to further elucidate the role of MEK4 in disease states, molecular probes are needed. To date, only a handful MEK4 inhibitors have been reported in the literature, with our preliminary report showcasing one of the most potent and selective inhibitors. We believe further refinement of our MEK4 inhibitors will allow us to better interrogate the role of MEK4 within the context of metastatic cancers. Herein, we describe progress towards the development of novel, cell-permeable MEK4 inhibitors and using our new probe compounds to provide insights into the roles of MEK4.

Design, synthesis, and evaluation of novel MEK4 inhibitors against pancreatic adenocarcinoma

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.