The Design, Synthesis and Biological Evaluation of Novel Histone Deacetylase Inhibitors Towards the Treatment of Solid Tumours.

Histone deacetylases (HDACs) form the catalytic core of large protein complexes involved in gene and protein regulation, and are considered to be among the most promising targets in drug development for cancer therapy. The HDAC family comprises four distinct groups, with class I, II and IV being Zn2+-dependent amidohydralases. The majority of therapeutic programmes have focused on modulation of chromatin conformation and consequent transcriptional activity, a mechanism centrally regulated by the class I HDAC subfamily. However, most of the current HDAC inhibitors (HDACi) are non-selective, being hindered by significant dose-limiting toxicity and lower than predicted efficacy.

It is now known that there are intrinsic differences in structure, function and role between the HDAC classes, a factor underpinning the issues with pan-HDACi. Whereas class I HDACs are nuclear and directly modulate gene expression, the class II family localise to the nucleus and cytoplasm where they are involved in protein folding and turnover, post-translational protein regulation, and nuclear-cytoplasmic shuffling. The class IIa subdivision of this family exhibit low enzymatic activity, and act as signalling regulators, multiprotein scaffolds, or “readers” of post-translational protein modifications. In the cancer context, the class IIa member HDAC7 is now known to play a major role in maintaining vascular integrity and driving angiogenesis, regulating endothelial cell migration in response to the pro-angiogenic vascular endothelial growth factor (VEGF). Specific deletion of HDAC7 from endothelial cells causes alteration of cell morphology and migration, leading to consequent dilation and rupture of blood vessels. During embryogenesis, HDAC7 is specifically expressed in vascular endothelium, and HDAC7-null mice are embryonic lethal due to a failure of vasculogenesis and endothelial cell-cell adhesion. We and others have demonstrated significant elevated expression of HDAC7 in several human cancer types, relative to the associated normal tissues. Several studies have now also shown that broad spectrum HDACi disturb the pro- and anti-angiogenic factor balance, an effect which we find is not observed with class I selective HDACi. Consequently, development of HDAC7-selective inhibitors holds significant potential as a novel antiangiogenic approach and efficacious therapeutic strategy, with reduced toxicity liability, for treatment of cancer.

Key research goals/questions
(1) The overall objective is to develop a selective HDAC7i (histone deactylase 7 inhibitor) clinical candidate as an anti-angiogenic therapeutic for the treatment of solid tumours. The drug developed should have improved selectivity, potency and pharmacological properties over existing HDACis.
(2) What are the outcomes of up or down regulating HDAC7 with respect to tumour growth and proliferation? Do the knock-on effects alter other cell differentiation, immunological responses and metabolic homeostasis?