Selective HDAC6 Inhibitors for Neurodegenerative Disease


HDAC6 plays an important role in neurological, inflammatory, and other diseases; and thus is an important target for therapeutic intervention.  To date, there are no FDA-approved HDAC6-targeting drugs and most pipeline candidates suffer from poor target engagement, inadequate brain penetration, and low tolerability. There are five HDAC6 clinical candidates for the treatment of mostly non-CNS cancers as their pharmacokinetic liabilities exclude them from targeting HDAC6-implicated neurological diseases, urging for the development to address these challenges. They also demonstrate off-target toxicity due to limited selectivity, leading to adverse effects in patients. Selective inhibitors have thus been the focus of development over the past decade, though no selective and potent HDAC6 inhibitor has yet been approved to date.



Researchers at the University of Toronto have used a rational, iterative approach to design a 2-site binding mechanism to target HDAC6, which has generated a platform that is the first to overcome core drug-design challenges such as weak binding, off-target toxicities, and poor pharmacokinetic profiles. (Figure 1). HDAX has also designed blood-brain-barrier crossing HDAC6 inhibitors, enabling CNS disease targeting that is not possible with competing molecules.  Additional applications possible in Charcot-Marie-Tooth (CMT), neurodegeneration, and heart failure.