A Chimeric SERM-Histone Deacetylase Inhibitor Approach to Breast Cancer Therapy

• Published in: ChemMedChem 2014-03, Vol.9 (3), p.602-613
• Main Authors: Patel, Hitisha K., Siklos, Marton I., Abdelkarim, Hazem, Mendonca, Emma L., Vaidya, Aditya, Petukhov, Pavel A., Thatcher, Gregory R. J.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Cell Death - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; estrogen receptors; HDAC inhibitors; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; histone deacetylases; Histone Deacetylases - metabolism; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; MCF-7 Cells; Molecular Structure; Selective Estrogen Receptor Modulators - chemical synthesis; Selective Estrogen Receptor Modulators - chemistry; Selective Estrogen Receptor Modulators - pharmacology; SERMs; Structure-Activity Relationship
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201300270

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 type I HDAC isoforms and antagonism of estrogenic activity in two cell lines yielded a SERMostat with 1–3 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. Two in one: The combination of HDAC inhibition and selective estrogen receptor modulation caused time‐dependent killing of breast cancer cells. A hybrid molecule, acting as HDAC inhibitor and selective estrogen receptor modulator (SERM), has potential, but can both activities be retained in killing ER (−) breast cancer cells?