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

Bioorg Med Chem. 2012 Oct 1;20(19):5901-14. doi: 10.1016/j.bmc.2012.07.048. Epub 2012 Aug 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / chemistry
  • Antioxidants / pharmacology
  • Apoptosis / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Dermatologic Agents / chemistry*
  • Dermatologic Agents / pharmacology*
  • Drug Design
  • ErbB Receptors / chemistry
  • ErbB Receptors / metabolism*
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • MAP Kinase Signaling System / drug effects
  • Protein Multimerization / drug effects*
  • Psoriasis / drug therapy*
  • Psoriasis / metabolism
  • Xanthines / chemistry*
  • Xanthines / pharmacology*

Substances

  • Antioxidants
  • Dermatologic Agents
  • Xanthines
  • ErbB Receptors