Abstract 5434: Development and biological characterization of novel, potent and stable isoform-specific inhibitors of histone deacetylase-8 (HDAC8)

Abstract

Abstract Histone deacetylase (HDAC) inhibitors have shown promise for the treatment of hematological and solid tumors. The current clinical candidates all inhibit multiple isoforms of the 11-member zinc-dependent HDAC family. With a view to increasing disease specificity and decreasing toxicity, we have developed potent and selective inhibitors of one isoform, HDAC8. We have previously described one such molecule, PCI-34051, which inhibited HDAC8 with a Ki of 10 nM and greater than 200-fold selectivity over other HDAC isoforms. However, this compound displayed poor metabolic stability and was not suitable for in vivo testing in animal models. We have therefore developed a series of analogs to increase metabolic stability while maintaining potency and isoform selectivity. These compounds, which are based on different pharmacophores, have similar potency and selectivity to PCI-34051 but have increased cellular potency, inhibiting cell growth and inducing apoptosis with EC50 of ∼1-2 μM in Jurkat and Hut78 lymphoma cells. These compounds also showed increased metabolic stability in an in-vitro rat liver microsomal assay. Since increased HDAC8 expression has recently been shown to be correlated with poor survival in neuroblastoma, the biological activities of these novel HDAC8 inhibitors were tested in neuroblastoma cell lines. Interestingly, these compounds were found to inhibit cell growth and induce differentiation in neuroblastoma cells. However, incubation with higher concentrations of these compounds did induce caspase activation and apoptosis in these cells. In keeping with the HDAC8 selectivity, no tubulin or histone acetylation was observed at upto 25μM. The best of these inhibitors is currently being tested in mouse xenograft models of T-cell lymphoma as well as neuroblastoma and the results will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5434.