Thienoquinolines as Novel Disruptors of the PKC蔚/RACK2 Protein鈥揚rotein Interaction

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• 作者：Florian Rechfeld ; Peter Gruber ; Johannes Kirchmair ; Markus Boehler ; Nina Hauser ; Georg Hechenberger ; Dorota Garczarczyk ; Gennady B. Lapa ; Maria N. Preobrazhenskaya ; Peter Goekjian ; Thierry Langer ; Johann Hofmann
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 24, 2014
• 年：2014
• 卷：57
• 期：8
• 页码：3235-3246
• 全文大小：690K
• 年卷期：v.57,no.8(April 24, 2014)
• ISSN：1520-4804

文摘

Ten protein kinase C (PKC) isozymes play divergent roles in signal transduction. Because of sequence similarities, it is particularly difficult to generate isozyme-selective small molecule inhibitors. In order to identify such a selective binder, we derived a pharmacophore model from the peptide EAVSLKPT, a fragment of PKC蔚 that inhibits the interaction of PKC蔚 and receptor for activated C-kinase 2 (RACK2). A database of 330鈥?00 molecules was screened in silico, leading to the discovery of a series of thienoquinolines that disrupt the interaction of PKC蔚 with RACK2 in vitro. The most active molecule, N-(3-acetylphenyl)-9-amino-2,3-dihydro-1,4-dioxino[2,3-g]thieno[2,3-b]quinoline-8-carboxamide (8), inhibited this interaction with a measured IC₅₀ of 5.9 渭M and the phosphorylation of downstream target Elk-1 in HeLa cells with an IC₅₀ of 11.2 渭M. Compound 8 interfered with MARCKS phosphorylation and TPA-induced translocation of PKC蔚 (but not that of PKC未) from the cytosol to the membrane. The compound reduced the migration of HeLa cells into a gap, reduced invasion through a reconstituted basement membrane matrix, and inhibited angiogenesis in a chicken egg assay.