Synthesis, and Evaluation of Potent and Selective MEK4 Inhibitors as a Targeted Therapeutic for Metastatic Pancreatic Ductal Adenocarcinoma

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Project Summary Pancreatic ductal adenocarcinoma (PDAC) is a deadly and common form of pancreatic cancer with an extremely low rate of survival. Due to the lack of distinct early-stage symptoms, most patients present with metastatic PDAC at the time of diagnosis. With limited effective treatments available for metastatic PDAC, and surgery being the only curative treatment, the US has recently seen an increasing number of fatalities due to PDAC. Matrix metalloproteinase-2 (MMP-2), a metalloproteinase directly associated with the development of metastatic cancers, has been heavily studied as a therapeutic target for stopping metastasis. However, MMP-2 inhibitors have failed in clinical trials, largely due to low efficacy and high toxicity. We propose that a focus on enzymes upstream from MMP-2 will allow for the development of more effective therapies for PDAC. Probing one such enzyme, MEK4 (otherwise known as MAP2K4), would give crucial insight into its role in proliferating metastatic PDAC. Increased expression of MEK4 has already been observed to increase metastasis in PDAC in multiple in vitro and in vivo studies. Unfortunately, no chemical probes for MEK4 currently exist. Leveraging our published platform for interrogating inhibitor selectivity across the MEK kinase family, as well as our published work on developing an initial lead for MEK4, this proposal is focused on filling this gap. As a multidisciplinary training platform utilizing synthetic organic chemistry, computational modeling, medicinal chemistry, in vitro biological assays, X-ray crystallography, molecular biology, and cancer models, the studies described in this proposal aim to provide new insights into the roles of MEK4 in regulating metastasis. Working with my sponsor, Prof. Scheidt, will provide intensive training in chemical synthesis, while my co-sponsor, Prof. Munshi, will provide similarly comprehensive training in cancer biology and its associated techniques. This research will be carried out as part of a collaborative effort between the Northwestern University Department of Chemistry and the Feinberg School of Medicine (Hematology and Oncology and Lurie Cancer Center), with further support from outside collaborators. Through this collaborative effort, I will develop the knowledge and skills to efficiently and effectively design experiments that bridge chemistry and biology. Ultimately, these studies will survey the efficacy of MEK4 inhibitors as targeted therapies for PDAC.