Abstract 24: Novel STAT3 & HDAC inhibitors that selectively target triple-negative breast cancer cell

Abstract

Abstract Signal transducer and activator of transcription 3 (STAT3) is an oncogenetic transcriptional factor which can modulate cancer cells apoptosis. Stimulation of cancer cells by cytokines such as IL-6, INF-a, etc., can induce phosphorylation of STAT3, resulting in the translocation of p-STAT3 into the nucleus where it facilitates the expression of anti-apoptosis genes. This p-STAT3 anti-apoptotic activity is one drug resistance mechanism developed by cancer cells against chemotherapies including histone deacetylase inhibitors (HDACi). Pyrimethamine has been reported to inhibit STAT3 phosphorylation, mRNA transcriptional level, and STAT3-dependent cell viabilities. In this presentation, we disclosed novel pyrimethamine-based bifunctional STAT3-HDAC inhibitors as potential therapeutic agents for p-STAT3-dependent cancers. We will describe the design, synthesis and biological activities of STAT3-HDAC inhibitors. We will show that these bifunctional agents inhibit HDAC deacetylase activity and STAT3 phosphorylation. A subset of these compounds is more cytotoxic to MDA-MB-231, a triple-negative breast cancer cell line that is highly dependent on STAT3. Citation Format: Bocheng Wu. Novel STAT3 & HDAC inhibitors that selectively target triple-negative breast cancer cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 24.