Characterization of CNS-Penetrant HDAC11-Selective Inhibitors in Alzheimer’s Disease Models

2023, 2024


Alzheimer’s disease (AD) is a major public health threat, a common neurodegenerative disorder, and the primary cause of dementia. The etiology of AD has not been completely elucidated, and there has yet to yield an effective therapy that can prevent, stop, or reverse cognitive deficits associated with AD. Epigenetics refers to functional modifications to the genome that do not involve a change in the DNA sequence. Epigenetics has become an attractive field in recent years within the drug discovery research communities. Recent studies have provided robust evidence for the involvement of histone deacetylases (HDACs) in various neurological diseases, including AD. Collective data support the promise of developing pharmacological agents that may modulate epigenetic biology and attenuate Alzheimer’s pathological alternations. This project is focused on HDAC11, which is the most recently identified member of the HDAC family. It displays functions closely related to human pathophysiology and has been shown as a potential drug target for AD. Here, we investigate a promising HDAC11-selective inhibitor PB94, focusing on further optimization to generate new analogs with good safety as well as strong efficacy in reducing Alzheimer’s neuropathological alternations. We showed that PB94 and its analogs displayed good safety profiles and significant anti-AD effects, which support our new molecules as potential therapeutics for AD.


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.

Funding to Date



Drug Development, Preclinical Drug Development


Can (Martin) Zhang, M.D., Ph.D.

Changning Wang, Ph.D.