Metastatic prostate cancer is not curable, and mortality primarily results from the development of distant metastases. Similarly, over 80% of deaths across all cancer types stem from the formation of metastases, and therefore effective anti-metastatic treatments would have enormous clinical benefit. Unfortunately, therapeutic approaches have been limited by a lack of potent and selective molecules targeting the underlying molecular processes that regulate metastasis. Using genetic and chemical methods in mouse and man, we have identified MAP2K4 as a key regulator of metastasis. The goal of this proposal is to identify and characterize selective MAP2K4 inhibitors that would serve as probes to validate the role of this kinase in an array of invasive cancer disease models. In preliminary work, we developed a functional kinase assay for HTS (Z' 0.58) and performed a pilot screen confirming our ability to identify MAP2K4 inhibitors (1.1% hit rate). We have also developed orthogonal biochemical and cellular assays to characterize the selectivity, mechanism, and anti-metastatic potential of HTS hits. Through this proposal we will: 1) Screen a library of 190,000 diverse compounds to identify functional MAP2K4 inhibitors; 2) Confirm MAP2K4 inhibition and selectivity using biochemical assays and validate promising hit scaffolds through analog synthesis; and 3) evaluate cellular activity of hits to determine potency, selectivity, and anti-metastatic properties. We predict that our integrative approach will enable discovery of new MAP2K4 inhibitors, which will provide the biological community with tools to evaluate the role of metastasis in a range of disease models. Furthermore, such molecules will serve as a starting point in future lead optimization studies to create anti- metastatic clinical candidates.
Metastatic prostate cancer (PCa) is not curable, and like most cancers the vast majority of deaths result from the development of distant metastases. Targeting key molecular processes that regulate metastasis could significantly improve advanced PCa mortality, but such anti-metastatic treatments do not currently exist. We have identified the MAP2K4 protein as a critical mediator of metastasis in PCa and propose high throughput screening to identify inhibitors that could lead to development of first generation anti metastatic agents.
|Deibler, Kristine K; Mishra, Rama K; Clutter, Matthew R et al. (2017) A Chemical Probe Strategy for Interrogating Inhibitor Selectivity Across the MEK Kinase Family. ACS Chem Biol 12:1245-1256|