Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis
| Autor: | Rosaleen J. Anderson, Donna Petch, Paul W. Groundwater, Simon P. Mackay, Ran Liu, Suja E. George, Andrew Paul, David A. P. Small, David E. Hibbs, Anne E. Cunningham |
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| Rok vydání: | 2012 |
| Předmět: |
Keratinocytes
MAPK/ERK pathway MAP Kinase Signaling System Clinical Biochemistry Pharmaceutical Science Apoptosis Caspase 3 Pharmacology Biochemistry Antioxidants Cell Line Annexin Drug Discovery Dithranol medicine Humans Psoriasis Molecular Biology Cell Proliferation Chemistry Organic Chemistry Molecular biology ErbB Receptors HaCaT medicine.anatomical_structure Cell culture Drug Design Xanthines Molecular Medicine Dermatologic Agents Protein Multimerization Keratinocyte medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 20:5901-5914 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2012.07.048 |
| Popis: | Hit compounds from in silico screening for inhibitors of the EGFR dimerization process were evaluated for their anti-proliferative (CCD-1106 keratinocytes) and anti-oxidant (TBA assay) activity and their effect on EGFR dimerization (BS(3) chemical crosslinking assay). 7-Benzyl-8-{N'-[1-(3-ethoxy-4-hydroxyphenyl)meth-(Z)-ylidene]hydrazino}-1,3-dimethylxanthine 2a (127 μM) leads to 37% inhibition of p-EGFR dimerization in the CCD-1106 cell line and also inhibits phosphorylation of proteins in the MAPK/ERK pathway, ERK 1/2 and p-38. Based on this initial data, 2a was selected for further study and was evaluated for its anti-proliferative activity in a range of keratinocyte (CCD-1106, HaCaT and NHEK) and monocyte (ThP1 and U937) cell lines. Xanthine 2a is pro-apoptotic in HaCaT keratinocytes, as shown by electron microscopy, caspase 3/7, and annexin V-FITC/PI flow cytometric assays. It is significantly less cytotoxic than the established antipsoriatic agent dithranol 14, as determined by MTT and LDH release assays, and thus has potential as a lead compound for the treatment of psoriasis. |
| Databáze: | OpenAIRE |
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