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 protein is 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, causing negatively charged DNA to wrap more tightly around them. This limits access to certain genes and, consequently, reduces their expression. Since genetic deficiency or inhibition of HDACs improves memory and cognition in Alzheimer’s mouse models, and given the neuropathological alterations of HDACs in AD brains, some scientists believe that elevated HDAC activity disrupts the expression of genes involved in learning and memory and contributes 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 that 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 reduces amyloid pathology and neuroinflammation. Recently, the team optimized a next-generation derivative of PB94, called PB151, and in their last CureAlz funding cycle, demonstrated that it reduced tau pathology while also improving cognitive function. In the current proposal, 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. Overall, this proposal represents another key step in developing an HDAC11 inhibitor that could potentially reach clinical trials.
