Alzheimer’s disease (AD) is a major public health threat, a common neurodegenerative disorder and the primary cause of dementia. Although decades of research in both industry and academia have improved the understanding of AD, they have yet to yield effective therapies that can prevent, stop or reverse the neuropathology and cognitive deficits associated with AD. The etiology of AD is complex and involves a multitude of genetic and epigenetic heterogeneity, which may display various mechanisms leading to the formation of amyloid plaque and neurofibrillary tangles, the two primary pathological hallmarks of AD in the brain. Because AD displays a magnitude of complex etiologies, there is a great need to develop interventions of different modalities and mechanisms of action.
Over the past decade, scientists have found that epigenetic enzymes, particularly histone deacetylases (HDACs), are promising targets for developing potential therapeutics for neurological conditions. Many epigenetic regulatory small molecules have been developed and used as FDA-approved drugs or are undergoing clinical trials. Recently, there has been keen interest in pharmacological approaches to inhibit HDACs for clinical intervention. HDAC11 is the most recently identified member in the HDAC family. It displays clinical significance with its functions closely related to human pathophysiology. We have synthesized a viable library of HDAC inhibitors and identified one promising HDAC11-selective inhibitor (PB94). As our current lead molecule, PB94 reduced the amyloid neuropathology and neuroinflammation in a mouse model expressing familial Alzheimer’s disease mutations in amyloid precursor protein (APP) and presenilin 1 (PSEN1) by biochemical and molecular imaging studies, suggesting its strong potential as an AD therapeutic. The goal of this project is to further optimize and characterize our lead molecule PB94, which ultimately may advance the drug development for AD and may allow us to uncover useful brain-penetrant HDAC11-selective inhibitors as potential AD therapeutics.