Identification of quinones as HER2 inhibitors for the treatment of trastuzumab resistant breast cancer

Bioorg Med Chem Lett. 2014 Jan 1;24(1):126-31. doi: 10.1016/j.bmcl.2013.11.064. Epub 2013 Dec 3.

Abstract

HER2 overexpression is associated with aggressive breast cancer with high recurrence rate and poor patient prognosis. Treatment of HER2 overexpressing patients with the HER2 targeting therapy trastuzumab results in acquired resistance within a year. The HER2/EGFR dual kinase inhibitor lapatinib was shown to inhibit some trastuzumab resistant breast cancer cell lines and is currently in clinical trials. Our group has found two new quinone compounds that show excellent inhibition of breast tumor cells expressing HER2 or the trastuzumab resistant HER2 oncogenic isoform, HER2Δ16. Compound 4 ((1R,2S,3S)-1,2,3,5,8-pentahydroxy-1,2,3,4-tetrahydroanthracene-9,10-dione) and compound 5 (5,8-dihydroxy-2,3-bis(hydroxymethyl)naphthalene-1,4-dione) showed sub-micromolar inhibition potency against these cell lines. These compounds also inhibit auto-phosphorylation of the Y1248 and Y1068 residues of HER2 and EGFR, respectively.

Keywords: Breast cancer; Docking studies; Emodin; HER2Δ16; Human epidermal growth factor receptor 2 (HER2); Phosphorylation; Quinones; Tyrosine kinase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • High-Throughput Screening Assays
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Quinones / chemistry
  • Quinones / pharmacology*
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / metabolism
  • Structure-Activity Relationship
  • Trastuzumab

Substances

  • Antibodies, Monoclonal, Humanized
  • Quinones
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab