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Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis

Petch, Donna and Anderson, Rosaleen J. and Cunningham, Anne and George, Suja E. and Hibbs, David E. and Liu, Ran and Mackay, Simon P. and Paul, Andrew and Small, David A. P. and Groundwater, Paul W. (2012) Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis. Bioorganic and Medicinal Chemistry, 20 (19). pp. 5901-5914. ISSN 0968-0896

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Abstract

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 (BS3 chemical crosslinking assay). 7-Benzyl-8-{N'-[1-( 3-ethoxy-4-hydroxyphenyl)meth-(Z)-ylidene]hydrazino}-1,3-dimethylxanthine 2a (127 mu M) 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.