A Chimeric SERM–Histone Deacetylase Inhibitor Approach to Breast Cancer Therapy. Issue 3 (16th August 2013)

• Record Type: Journal Article
• Authors: Patel, Hitisha K.; Siklos, Marton I.; Abdelkarim, Hazem; Mendonca, Emma L.; Vaidya, Aditya; Petukhov, Pavel A.; Thatcher, Gregory R. J.
• Is Part Of: ChemMedChem. Volume 9:Issue 3(2014:Mar.)
• Page Start: 602
• Page End: 613
• Publication Date: 2013-08-16
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201300270
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 μ<sc>M</sc> 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.</p> </abstract>