Prolonged Histone Hyperacetylation With A Novel Class Of Hdac1/2 Selective Inhibitors

The histone deacetylase (HDAC) metalloenzymes are intricately involved in gene expression through epigenetic regulation of histone acetylation. They also regulate the acetylation status of numerous non-histone proteins such as transcription factors p53, STAT1 and NF-κB as well as α-tubulin, Hsp90 and Ku70. Of the eleven zinc-dependent HDAC enzymes identified, HDACs 1 and 2 appear to be most critical in oncogenesis and tumor maintenance. They are overexpressed in many human cancers and RNAi knockdown leads to increased apoptosis. We recently disclosed a family of novel HDAC1/HDAC2-selective biaryl inhibitors. In this presentation, we will describe unique features of these biaryl inhibitors that contribute to improved preclinical efficacy and tolerability. Desirable HDAC inhibitor properties identified from preclinical experience with Zolinza™ include subtype selectivity toward HDAC1/HDAC2 and prolonged target inhibition. Compelling in vitro and in vivo data indicates that solid tumor cell lines are most sensitive to HDAC inhibition under continuous exposure rather than intermittent exposure. These biaryl inhibitors exhibit extended target engagement in vivo, and are well tolerated in nude mice. Unlike other known HDAC inhibitors, these compounds exhibit a delay in and prolongation of histone hyperacetylation in nude mice bearing HCT116 tumors, extending beyond plasma clearance of the drug. 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 5433.