A Chimeric SERM-histone deacetylase inhibitor approach to breast cancer therapy

Hitisha K. Patel, Marton I. Siklos, Hazem Abdelkarim, Emma L. Mendonca, Aditya Vaidya, Pavel A. Petukhov, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Breast cancer remains a significant cause of death in women, and few therapeutic options exist for estrogen receptor negative (ER (-)) cancers. Epigenetic reactivation of target genes using histone deacetylase (HDAC) inhibitors has been proposed in ER (-) cancers to resensitize to therapy using selective estrogen receptor modulators (SERMs) that are effective in ER (+) cancer treatment. Based upon preliminary studies in ER (+) and ER (-) breast cancer cells treated with combinations of HDAC inhibitors and SERMs, hybrid drugs, termed SERMostats, were designed with computational guidance. Assay for inhibition of four typea I HDAC isoforms and antagonism of estrogenic activity in two cell lines yielded a SERMostat with 1-3a μM potency across all targets. The superior hybrid caused significant cell death in ER (-) human breast cancer cells and elicited cell death at the same concentration as the parent SERM in combination treatment and at an earlier time point.

Original languageEnglish (US)
Pages (from-to)602-613
Number of pages12
JournalChemMedChem
Volume9
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

Keywords

  • breast cancer
  • estrogen receptors
  • HDAC inhibitors
  • histone deacetylases
  • SERMs

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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