Abstract LB-8: Design and development of a novel series of HDAC6-selective inhibitors for the treatment of cancer

Inhibition of the zinc-dependent histone deacetylase (HDAC) family of enzymes has been pursued as a clinical strategy in cancer for over a decade. HDACs regulate the expression and activity of numerous proteins involved in both cancer initiation and cancer progression; by removal of acetyl groups from histones, HDACs create a non-permissive chromatin conformation that prevents the transcription of genes that encode proteins involved in tumorigenesis. The current landscape of HDAC-targeting therapeutics has, however, been dominated by pan-inhibitors that regulate the activity of most, if not all, of the HDAC family members which, through dysregulation of expression of a myriad of genes, has led to agents with undesirable toxicities and narrow therapeutic margins. Recently, however, attention has begun to turn to the role of specific HDAC isoforms in tumorigenesis and, in turn, the development of more selective therapeutics. HDAC6 has emerged as a particularly interesting target as it plays an essential role in aggresomal protein degradation: specifically, HDAC6 binds polyubiquitinated misfolded proteins and recruits misfolded protein cargo to dynein motors for transport to aggresomes. Cells deficient in HDAC6 fail to clear these misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins, which leads to activation of apoptosis. This presentation will outline the design and development of a new class of highly-potent, selective and orally-active HDAC6 inhibitors with the potential in the treatment of multiple tumor types. Uniquely, this series of compounds has been designed such that selectivity levels for HDAC6 over other isoforms can be finely regulated, enabling the investigation of preferred levels of HDAC6 specificity for therapy. Citation Format: Stephen J. Shuttleworth. Design and development of a novel series of HDAC6-selective inhibitors for the treatment of cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-8. doi:10.1158/1538-7445.AM2014-LB-8