Inhibition of protein-protein interactions in the extracellular signal-regulated kinase (ERK)

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Alba T. Macias, alba_macias@hotmail.com, Chad N Hancock, Eun Kyoung Lee, Su Yeon Yu, Alexander D. MacKerell Jr., alex@outerbanks.umaryland.edu, and Paul Shapiro. Department of Pharmaceutical Sciences, University of Maryland at Baltimore, 20 South Penn Street, Baltimore, MD 21201
The extracellular signal regulated kinases (ERK1/ERK2) signal transduction pathways play a critical role in cell proliferation. Hyper-activation of ERK is thought to be involved in many human cancers. Thus, inhibition of ERK signaling could be an approach to prevent cancer cell proliferation. Currently, no specific inhibitors of the ERK proteins exist. Known kinase inhibitors lack specificity for ERK because they target the ATP binding region which is well conserved among protein kinases. We targeted a protein-protein docking site using computer-aided drug design (CADD). Following a CADD screen of over 800,000 molecules, 80 potential small molecular weight compounds were tested for activity in biological assays. Several compounds inhibited ERK-specific phosphorylation of Rsk-1 or Elk-1, two substrates of ERK involved in cell proliferation. Direct binding between the compounds and ERK2 was indicated by fluorescence quenching and active compounds showed a dose dependent reduction in the proliferation of several cancer cell lines.