Prostate cancer (PCa) is currently the most commonly diagnosed cancer in American males. Mortality from this disease is primarily due to the development of distant metastases, accounting for over 80% of all cancer deaths. Consequently, the attenuation of cancer cell movement and metastasis is a critical unmet medical need with broad potential impact. MEK4 is a dual-specificity kinase that is upstream in the p38 MAPK pathway. In advanced PCa lesions, MEK4 is overexpressed and induces metastasis. It has been shown that MEK4 increases the invasive potential of PCa cells in vitro by upregulating the production of matrix metalloproteinase 2 (MMP-2), and also leads to increased metastasis in an in vivo mouse model. However, selective MEK4 inhibitors that could unambiguously validate this target do not exist. To address this gap in the knowledge, the aim of this research is to combine chemical synthesis and biological evaluation to discover new chemical probes to enhance our understanding of MEK4 function in human PCa cell invasion and metastasis. In order to accomplish this goal we have utilized NMR spectroscopy techniques, including Waterlogsy and saturation transfer difference, to understand the binding modes of active compounds. This empirical data is ultimately being used to improve computational models and guide further chemical optimization. We have focused on developing an efficient profiling platform against the MEK isoforms to address the selectivity challenges associated with developing new kinase inhibitors. The work presented utilizes known kinase inhibitors, originally shown to have off-target effects on MEK4, to develop a structural understanding of MEK4; the work further progresses into the analysis of MEK isoform selectivity and the current development of MEK4 selective chemical probes.

Chemical probe approach to elucidate the role of MEK4 in metastasis

251st National Meeting (2016)

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