# Mechanistic Validation of Selective Brain-Penetrant HDAC6 Inhibitors as a Disease- Modifying Treatment for Tauopathies including Alzheimer's Disease

> **NIH NIH R43** · EIKONIZO THERAPEUTICS, INC. · 2020 · $509,672

## Abstract

PROJECT SUMMARY
Significance: Disease-delaying or -preventing therapies are desperately needed for Alzheimer’s disease (AD).
Unfortunately, most AD therapeutics in development have focused on amyloid, based on the observed plaques
in AD patients. These efforts have been unsuccessful thus far, pointing to the need to develop other promising
targets. Tau is emerging as a more hopeful therapeutic target for AD because tau neurofibrillary tangles (NFTs)
are not only a hallmark of AD and other tauopathies, but also correlate with cognitive decline more closely than
amyloid. In contrast to pharma’s current efforts to target tau through immunotherapy, Eikonizo’s approach uses
small molecules to target tau pathology through a completely different mechanism.
Hypothesis: We hypothesize that inhibiting the enzyme histone deacetylase 6 (HDAC6) will positively modify
tau to prevent tau aggregation. Beyond modifying tau, inhibiting HDAC6 will also promote degradation of HSP90
client proteins, including tau, and improve microtubule function required for mitochondrial and axonal transport
– which are also known to be disrupted in AD.
Preliminary Data: Eikonizo’s initial lead compound, EKZ-001, is superior to all other reported HDAC6 inhibitors
for CNS indications with high potency (IC50 15 nM), high selectivity (>100-fold over related isoforms) and high
brain penetration (brain:plasma >8). EKZ-001 demonstrates HDAC6 mechanistic engagement in human neural
progenitor cells and critically does not target histone-modifying HDACs, thus avoiding known dose-limiting
liabilities of pan-HDAC inhibitor therapeutics. EKZ-001 also lowers tau aggregation in primary mouse neurons
exposed to β-amyloid. Eikonizo has proprietary technology to validate target engagement through a companion
HDAC6 positron emission tomography (PET) imaging agent and we have demonstrated that EKZ-001 blocks
HDAC6 PET signal in vivo in the brain of non-human primates. Eikonizo has synthesized improved, drug-like
derivatives of EKZ-001 for testing in cellular and preclinical proof-of-mechanism experiments.
Specific Aims: This study will evaluate drug-like lead compounds derived from EKZ-001 in primary neurons and
in vivo in a mouse model of AD to demonstrate proof-of-mechanism. Following treatment with EKZ compounds,
molecular markers of HDAC6 mechanistic engagement will be confirmed in primary hippocampal neurons
(Aim1), and the two top lead compounds will be tested in PS19 mice, in vivo (Aim 2). Successful completion of
the proposed Aims will be a major step towards IND-enabling studies of the development candidate for a first-
in-human and first-in-class trial of an HDAC6 inhibitor as a therapeutic for tauopathies including AD.
Milestones for Progression to Phase II: 1) proof-of-mechanism and 2) favorable PK profile for lead compound
to be advanced to IND-enabling studies. [Specific, quantitative targets included in Aims and Research Strategy.]

## Key facts

- **NIH application ID:** 10137813
- **Project number:** 1R43AG067939-01A1
- **Recipient organization:** EIKONIZO THERAPEUTICS, INC.
- **Principal Investigator:** Frederick Albert Schroeder
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $509,672
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137813

## Citation

> US National Institutes of Health, RePORTER application 10137813, Mechanistic Validation of Selective Brain-Penetrant HDAC6 Inhibitors as a Disease- Modifying Treatment for Tauopathies including Alzheimer's Disease (1R43AG067939-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10137813. Licensed CC0.

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