Mitogen-activated protein kinase kinase 5 (MEK5) is a component of mitogen-activated protein kinase (MAPK) signaling pathways. Mitogen-activated protein kinase kinase kinase 2 (MEKK2) activates MEK5, which in turn activates Extracellular signal-Regulated Kinase (ERK5) forming a three-tiered phosphorylation cascade. Activated pERK5 activates transcription factors to increase cell proliferation, cell growth, cell differentiation, and angiogenesis. MEK5/ERK5 signaling is upregulated in various cancers, such as breast cancers, prostate cancers, and colon cancers; hyper-activation of MEK5 is correlated with poor prognosis for these cancers. Despite this strong correlation, selective MEK5 inhibitors have remained under-explored.<br/>Using the x-ray crystal structure of MEK1 (PDB: 3SLS) bound to inhibitor <b>1</b>, a homology model of MEK5 was constructed. Based on the homology model and the previous SAR knowledge, series of thiophene analogs were designed for selective allosteric inhibition of MEK5. The design, synthesis, and biological activity will be presented.

Selective allosteric inhibition of MEK5: novel target for cancer therapeutics

256th National Meeting (2018)

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