title: Design and synthesis of EGFR dimerization inhibitors and evaluation of their potential in the treatment of psoriasis.
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 (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.
authors.affiliation: Sunderland Pharmacy School, University of Sunderland, Wharncliffe Street, Sunderland, SR1 3SD, UK.
authors.forename: Donna
authors.initials: D
authors.lastname: Petch
authors.forename: Rosaleen J
authors.initials: RJ
authors.lastname: Anderson
authors.forename: Anne
authors.initials: A
authors.lastname: Cunningham
authors.forename: Suja E
authors.initials: SE
authors.lastname: George
authors.forename: David E
authors.initials: DE
authors.lastname: Hibbs
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
authors.forename: Simon P
authors.initials: SP
authors.lastname: Mackay
authors.forename: Andrew
authors.initials: A
authors.lastname: Paul
authors.forename: David A P
authors.initials: DA
authors.lastname: Small
authors.forename: Paul W
authors.initials: PW
authors.lastname: Groundwater
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003879:Dermatologic Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects*; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism; D014970:Xanthines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D003879:Dermatologic Agents; D014970:Xanthines; D066246:ErbB Receptors