Abstract 5068: A novel dual action inhibitor of histone deacetylase and demethylase in melanoma

Abstract

Abstract Epigenetic agents have drawn great attention as anti-cancer therapies, with several HDAC inhibitors approved for a subset of hematologic malignancies. One of the biggest challenges in targeting epigenetic mechanisms of tumorigenesis is the wide spectrum of effects which restrict the therapeutic window for these compounds. We have developed a series of potent small molecule inhibitors with specificity towards the CoREST epigenetic corepressor complex through a dual-action mechanism targeting LSD1 and HDAC1. These compounds show a unique profile of pharmacologic action with an improved therapeutic window in a variety of cell types. Screening of tumor cell lines for growth inhibitory effects revealed variable efficacy in a broad spectrum of cancers with the most consistent and potent effects seen in human melanomas. The growth of a number of melanoma cell lines was found to be potently inhibited by one of these compounds, Corin 2; however, primary human melanocytes were relatively resistant to this agent. Transcriptomic analysis revealed that Corin2 was a more potent inducer of tumor suppressor genes compared to the parent HDAC and LSD1 compounds. Genetic knockdown of CoREST or LSD1 in cancer cell lines abolished the differences in potency of Corin2 vs. the parent HDAC inhibitor, Entinostat, suggesting that Corin2's favorable pharmacologic effects rely on an intact CoREST complex. Corin2 was also effective in slowing tumor growth in a melanoma mouse xenograft model. These dual action inhibitors demonstrate a novel, potent, and specific therapeutic approach to targeting epigenetic pathways in human melanomas which may lead to improved therapeutic benefits in patients with advanced disease. Note: This abstract was not presented at the meeting. Citation Format: Muzhou WU, Jay Kalin, Byungwoo Ryu, Philip Cole, Rhoda Alani. A novel dual action inhibitor of histone deacetylase and demethylase in melanoma [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 5068. doi:10.1158/1538-7445.AM2017-5068