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

作者：Patel Hitisha K; Siklos Marton I; Abdelkarim Hazem; Mendonca Emma L; Vaidya Aditya; Petukhov Pavel A; Thatcher Gregory R J^*

来源：ChemMedChem, 2014, 9(3): 602-613.

DOI：10.1002/cmdc.201300270

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

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 typeI HDAC isoforms and antagonism of estrogenic activity in two cell lines yielded a SERMostat with 1-3M 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.

• 出版日期2014-3