Identification of novel extracellular signal-regulated kinase docking domain inhibitors.

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TitleIdentification of novel extracellular signal-regulated kinase docking domain inhibitors.
Publication TypeJournal Article
Year of Publication2005
AuthorsHancock, CN, Macias, A, Lee, EKyoung, Yu, SYeon, Mackerell, AD, Shapiro, P
JournalJ Med Chem
Date Published2005 Jul 14
KeywordsBinding Sites, Cell Line, Tumor, Cell Proliferation, Computer Simulation, Databases, Factual, DNA-Binding Proteins, Drug Design, ets-Domain Protein Elk-1, Humans, Mitogen-Activated Protein Kinase 1, Models, Molecular, Molecular Structure, Phosphorylation, Protein Kinase Inhibitors, Protein Structure, Tertiary, Proto-Oncogene Proteins, Quantitative Structure-Activity Relationship, Ribosomal Protein S6 Kinases, 90-kDa, Transcription Factors

The extracellular signal regulated kinase (ERK1 and ERK2) signal transduction pathways play a critical role in cell proliferation. Hyperactivation of the ERK proteins either through increased expression of membrane-bound growth factor receptors or genetic mutations of upstream proteins is thought to be involved in the pathogenesis of many human cancers. Thus, targeted inhibition of ERK signaling is viewed as a potential approach to prevent cancer cell proliferation. Currently, no specific inhibitors of the ERK proteins exist. Moreover, most kinase inhibitors lack specificity because they target the ATP binding region, which is well conserved among the protein kinase families. Taking advantage of recently identified ERK docking domains, which are reported to facilitate substrate protein interactions, we have used computer-aided drug design (CADD) to identify novel small molecular weight ERK inhibitors. Following a CADD screen of over 800 000 molecules, 80 potential compounds were selected and tested for activity in biological assays. Several compounds inhibited ERK-specific phosphorylation of ribosomal S6 kinase-1 (Rsk-1) or the ternary complex factor Elk-1 (TCF/Elk-1), both of which are involved in promoting cell proliferation. Active compounds showed a dose-dependent reduction in the proliferation of several cancer cell lines as measured by colony survival assays. Direct binding between the active compounds and ERK2 was indicated by fluorescence quenching. These active compounds may serve as lead candidates for development of novel specific inhibitors of ERK-substrate interactions involved in cell proliferation.

Alternate JournalJ. Med. Chem.
PubMed ID15999996
Grant ListR21 CA105299 / CA / NCI NIH HHS / United States
CA095200-03S1 / CA / NCI NIH HHS / United States
CA105299-01 / CA / NCI NIH HHS / United States
CA95200-01 / CA / NCI NIH HHS / United States