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

Epigenetics refers to how cells modify gene expression without changing the DNA sequence. This regulation involves small chemical tags that attach to both regulatory and coding DNA. The tags alter how the DNA is read and mirror-copied into mRNA and can thus alter whether and how much proteins are made and even the structure of those proteins. However, since these changes do not alter the genetic code, they are reversible. Histone deacetylases (HDACs) are enzymes that control these changes and have been linked to Alzheimer’s disease (AD) and other neurodegenerative diseases. HDACs remove acetyl groups from histone proteins. DNA wraps around histones—proteins that help organize and compact genetic material—like thread around a spool. This packaging also regulates how accessible genes are to proteins involved in replication and translation. When HDACs remove acetyl groups from histones, the histones become more positively charged and cause negatively charged DNA to wrap more tightly around them, which limits access to certain genes and thus reduces their expression. Genetic deficiency or inhibition of HDACs in Alzheimer’s mouse models improves memory and cognition and, in combination with other evidence, e.g. neuropathological alteration of HDACs in AD brains. This has led some scientists to believe that in AD, HDAC activity particularly disrupts the expression of genes involved in learning and memory and leads to AD pathology. As a result, HDAC inhibitors have become an intriguing new area of focus as AD therapeutic targets.

With CureAlz support, Drs. Zhang and Wang have been developing brain-penetrant inhibitors of a specific HDAC: HDAC11. The team previously showed HDAC11 is elevated in post-mortem AD brains and co-localizes strongly with amyloid pathology. In a previous CureAlz grant cycle, the duo developed a library of HDAC11 inhibitors and identified a promising candidate that they named PB94. In AD mouse studies, they showed that PB94 binds to HDAC11 at a safe dosage and reduced amyloid pathology and neuroinflammation. Recently, the team optimized a next-gen derivative of PB94 called PB151, and in their last CureAlz funding cycle showed that it reduced tau pathology while also improving cognitive function.

In the current project, the team plans to complete their studies demonstrating the efficacy and safety of PB151 while also identifying new analogs of this promising inhibitor. The studies will confirm the ability of these potential inhibitors to successfully impact amyloid and tau pathology and if the new analogs are safe in key AD mouse models. The team will also delve more deeply into the mechanisms underlying HDAC11’s role in AD pathogenesis.

In the first year of funding, Drs. Zhang and Wang made strides in evaluating the safety and biochemical profile of PB151 and in demonstrating its efficacy across several mouse models of different AD pathologies. They assessed the level of off-target binding of the candidate drug to other proteins and found that PB151 was highly specific to HDAC11. They also employed a modeling platform to determine how PB151 binds to HDAC11, establishing the most critical interactions to its inhibitory action. This information will be valuable as the team develops improved versions of HDAC inhibitors. They have already generated several analogs for further testing while they continue to optimize PB151. In their mouse studies, the team found PB151 was effective in reducing tau pathology and restoring behavioral deficits. Importantly, they also showed a strong reduction of several key inflammatory markers. The team will continue their assessment of PB151 and the synthesized analogs in the second year of funding.

Overall, this proposal represents another key step toward developing an HDAC11 inhibitor that could enter clinical trials as a potential therapy in treating AD.