Despite its name, HDAC6 is primarily a tubulin deacetylase, not a histone deacetylase, and it has emerged as a particularly interesting – and unique – cancer target as it plays an essential role in stress response and 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. Further, recent evidence has emerged of HDAC6 modulating immune-related pathways in solid tumors, notably regulating PD-L1 expression through STAT3 modulation. In order to explore the clinical potential of HDAC6 in both hematological and solid tumor immunotherapy, we have de novo-designed a class of highly-potent, ultra-selective and orally-active HDAC6 inhibitors with potential in the treatment of multiple tumor types, including through immunotherapeutic mechanisms. Additionally, owing to the selectivity we have achieved for HDAC6 with our lead compounds, much greater opportunities for broader combination modalities can be realized, and we have established potentiation of our leads with other tumor immunotherapeutics in in vivo syngeneic models. The profile of our preclinical development candidate will be presented.
Citation Format: Stephen J. Shuttleworth. Design and development of HDAC6-selective inhibitors for hematological cancer treatment and solid tumor immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B009.