Abstract LB-308: Development of histone deacetylase 6 inhibitors: Effects of HDAC6 inhibitors in normal and cancer cells.

Abstract

Abstract Histone deacetylase 6 (HDAC6) is Class IIb deacetylase. HDAC6 is a cytoplasmic protein and has two catalytic domains, an ubiquitin binding domain, and a dynein binding domain. Its substrates include many non-histone proteins such as alpha-tubulin, HSP90, Ku-70 and peroxiredoxins but not histones. HDAC6 plays a role in oxidative stress response, cellular mobility, mitochondrial potential, protein-protein interactions, and aggresome formation in degradation pathways of misfolded proteins. These properties of HDAC6 make it an attractive target for development of an isoform-specific HDAC6 inhibitor that may have useful therapeutic applications for treating cancer as well as neurodegenerative diseases. Based on our experience in development of vorinostat, the pan-HDAC inhibitor, we have developed novel small molecules that selectively inhibit HDAC6. In our studies to date, at least three molecules have been discovered with high selectivity against HDAC6 based on both in vitro and in vivo studies. In vitro recombinant enzyme assay found that our novel compounds potently inhibit HDAC6, with approximately 50-fold selectivity against HDAC6 over HDAC1. Concentrations as high as 16 µM of the novel compounds induce accumulation of acetylated alpha-tubulin but not acetylated histones in normal (HFS; human foreskin fibroblast) and transformed (LNCaP; human prostate cancer, U87; human glioblastoma, A549; human lung adenocarcinoma) cells. There is no induced cell death and modest inhibition of cell proliferation. We tested the effect of our novel HDAC6 selective inhibitors in combination with DNA damaging anti-cancer drugs (etoposide, doxorubicin, or vorinostat) in normal (HFS) and transformed (LNCaP and U87) cells. There is no induced cell death in normal cells cultured with combination of a HDAC6 selective inhibitor and anti-cancer drugs. In transformed cells, combination of a HDAC6 inhibitor with etoposide, doxorubicin, or vorinostat enhanced cell death compared to either drug alone. In vivo studies in normal and immune-deficient mice found that the novel HDAC6 inhibitor is well tolerated in mice and selectively inhibit HDAC6 as indicated by accumulation of acetylated alpha-tubulin but not accumulation of acetylated histones in lung and spleen isolated from mice injected with HDAC6 selective inhibitors. These novel HDAC6-selective inhibitors we developed are potential candidates for combination therapy to enhance the potency of anticancer drugs such as etoposide or doxorubicin in human cancers. Citation Format: Ju-Hee Lee, Megan L. Choy, Lang Ngo, Gisela Venta-Perez, Mahendran Adaickapillai, Yuanshan Yao, Ronald Breslow, Paul A. Marks. Development of histone deacetylase 6 inhibitors: Effects of HDAC6 inhibitors in normal and cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-308. doi:10.1158/1538-7445.AM2013-LB-308