Computer-aided identification of novel anticancer compounds with a possible dual HER1/HER2 inhibition mechanism

Bioorg Med Chem Lett. 2015 Feb 15;25(4):758-62. doi: 10.1016/j.bmcl.2014.12.095. Epub 2015 Jan 6.

Abstract

HER1 and HER2 are frequently overexpressed in human tumors where they drive cellular proliferation. For this reason they are considered important targets in anticancer therapy with dual HER1/HER2 inhibitors being recently approved and marketed. In this paper we report the identification of a series of compounds with anticancer activity by a combined virtual screening approach on the kinase domains of HER1 and HER2. 6 hit compounds that present a sub- or low-micromolar activity in two cell-based assays, were initially identified and a subsequent design cycle led to the synthesis of a compound with nanomolar activity in the cell-based assays.

Keywords: HER1 EGFR; HER2; Virtual screening structure-based drug design.

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Computer-Aided Design
  • Drug Screening Assays, Antitumor / methods
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / chemistry
  • Female
  • Humans
  • Models, Molecular
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / chemistry

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2