Small-molecule inhibitors of ERK-mediated immediate early gene expression and proliferation of melanoma cells expressing mutated BRaf.

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TitleSmall-molecule inhibitors of ERK-mediated immediate early gene expression and proliferation of melanoma cells expressing mutated BRaf.
Publication TypeJournal Article
Year of Publication2015
AuthorsSamadani, R, Zhang, J, Brophy, A, Oashi, T, U Priyakumar, D, E Raman, P, St John, FJ, Jung, K-Y, Fletcher, S, Pozharski, E, Mackerell, AD, Shapiro, P
JournalBiochem J
Date Published2015 May 01
KeywordsAntineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Computer Simulation, Drug Design, Drug Screening Assays, Antitumor, Gene Expression, Genes, Immediate-Early, HeLa Cells, Humans, Jurkat Cells, Ligands, MAP Kinase Signaling System, Melanoma, Models, Molecular, Molecular Dynamics Simulation, Mutation, Phosphorylation, Promoter Regions, Genetic, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-fos, Serum Response Element, Transcription Factor AP-1

Constitutive activation of the extracellular-signal-regulated kinases 1 and 2 (ERK1/2) are central to regulating the proliferation and survival of many cancer cells. The current inhibitors of ERK1/2 target ATP binding or the catalytic site and are therefore limited in their utility for elucidating the complex biological roles of ERK1/2 through its phosphorylation and regulation of over 100 substrate proteins. To overcome this limitation, a combination of computational and experimental methods was used to identify low-molecular-mass inhibitors that are intended to target ERK1/2 substrate-docking domains and selectively interfere with ERK1/2 regulation of substrate proteins. In the present study, we report the identification and characterization of compounds with a thienyl benzenesulfonate scaffold that were designed to inhibit ERK1/2 substrates containing an F-site or DEF (docking site for ERK, FXF) motif. Experimental evidence shows the compounds inhibit the expression of F-site containing immediate early genes (IEGs) of the Fos family, including c-Fos and Fra1, and transcriptional regulation of the activator protein-1 (AP-1) complex. Moreover, this class of compounds selectively induces apoptosis in melanoma cells containing mutated BRaf and constitutively active ERK1/2 signalling, including melanoma cells that are inherently resistant to clinically relevant kinase inhibitors. These findings represent the identification and initial characterization of a novel class of compounds that inhibit ERK1/2 signalling functions and their potential utility for elucidating ERK1/2 and other signalling events that control the growth and survival of cancer cells containing elevated ERK1/2 activity.

Alternate JournalBiochem. J.
PubMed ID25695333
PubMed Central IDPMC4643458
Grant ListF31 GM100693 / GM / NIGMS NIH HHS / United States
P41 GM103393 / GM / NIGMS NIH HHS / United States
R01 CA120215 / CA / NCI NIH HHS / United States
R01CA120215 / CA / NCI NIH HHS / United States