Abstract LB-067: Design, synthesis and biological evaluation of novel selenocyanide histone deacetylase inhibitor as anti-triple negative breast cancer agents

Abstract

Abstract Approximate 70-80% of breast cancers are estrogen receptor positive (ER+), and the ERα plays essential role in breast cancer growth. Therefore, many ERα ligands have been developed for hormone drugs, such as tamoxifen, which is the first line drug for the treatment of ER(+) breast cancer. Unfortunately, endocrine therapy is ineffective for triple-negative breast cancer (TNBC), which lacks of expression of ER, PR and HER-2, representing about 20% of breast cancers. Current treatment option for TNBC is still limited to cytotoxic chemotherapy, and histone deacetylase inhibitor (HDACi) was used as novel therapeutic strategy for TNBC. HDACi can induce functional ERα re-expression and re-sensitize cells of TNBC to estradiol activator and tamoxifen antagonist. More than ten clinical trials of HDACi are underway for the treatment of TNBC, and most of HDAC inhibitors have the hydroxamic acid moiety, a typical zinc-binding group. However, these inhibitors do not show significant anticancer effects on TNBC compared to SAHA, which is the first HDACi approved by FDA. Hydroxamic acids usually have pharmacokinetic and metabolic problems, and also SAHA shows considerable toxicity to healthy cells. Therefore, much effort has been undertaken to develop an “ideal HDACi”, more effective and less toxic. We recently found that zinc-binding group of HDACi is selenocyanide (named as SelA), which shows strong anti-HDAC1, HDAC6 and HDAC8. These three isoforms have been found to be critical for the invasion and migration of both ER(+) breast cancer and TNBC activities, with a nanomolar range of IC50, and demonstrate high selectivity for HDAC6; moreover, SelA also displays significant anti-proliferative effect on both ER(+) breast cancer and TNBC both in vitro and in vivo. In summary, selenocyanide compound represents a novel HDACi for the treatment of TNBC, and the structure-activity relation is pursuing. Citation Format: Chu Tang, Yang Du, Jie Tian. Design, synthesis and biological evaluation of novel selenocyanide histone deacetylase inhibitor as anti-triple negative breast cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-067. doi:10.1158/1538-7445.AM2017-LB-067