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A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia
Rebecca E. James, Michael E. Bekier, P. Lee, Frederick A. Schroeder, Lauren Jayne Evans, Florence F. Wagner, Dean Hickman, Tom Richardson et al.. Brain, 2025-10-07
Topic: Brain proteins, microglia and lab models
We present the pharmacological properties of EKZ-438, which demonstrate high selectivity for HDAC6 (>8500-fold selectivity for HDAC6 versus all other HDAC6 paralogues), low nanomolar potency (12 nM) for HDAC6, and importantly, CNS-penetrance (unbound brain-to-plasma partition coefficient [Kp,uu,brain] ≥ 0.55) and high oral bioavailability (fraction of dose absorbed [F%] = 70). Notably, we extended these findings to human induced pluripotent stem cell-derived neuronal cellular models, supporting the relevance of our findings to human disease. We conclude that selective HDAC6 inhibition represents a promising therapeutic approach for potential disease modification in amyotrophic lateral sclerosis and frontotemporal dementia.
Key findings
- We present the pharmacological properties of EKZ-438, which demonstrate high selectivity for HDAC6 (>8500-fold selectivity for HDAC6 versus all other HDAC6 paralogues), low nanomolar potency (12 nM) for HDAC6, and importantly, CNS-penetrance (unbound brain-to-plasma partition coefficient [Kp,uu,brain] ≥ 0.55) and high oral bioavailability (fraction of dose absorbed [F%] = 70).
- Notably, we extended these findings to human induced pluripotent stem cell-derived neuronal cellular models, supporting the relevance of our findings to human disease.
- We conclude that selective HDAC6 inhibition represents a promising therapeutic approach for potential disease modification in amyotrophic lateral sclerosis and frontotemporal dementia.
Why it matters
This study presents the pharmacological properties of a next-generation HDAC6 inhibitor, EKZ-438, showing high selectivity, CNS-penetrance, and oral bioavailability in cellular models. It concludes that selective HDAC6 inhibition is a promising therapeutic approach for potential disease modification, but this is early preclinical work and not yet a treatment.
Study details
- Evidence strengthLow
How this study scored 43/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain) |
| Journal's citation record | 4 / 4 | Brain: journal h-index 503 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 7 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 7 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Tonya M. Gilbert: h-index 12 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Michigan: institution h-index 2,240 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41061670) |
| Free to read | 2 / 2 | Free to read |
| Total | 43 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
James, R. E., Bekier, M. E., Lee, P., Schroeder, F. A., Evans, L. J., Wagner, F. F., et al. (2025). A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia. Brain. https://doi.org/10.1093/brain/awaf380
Vancouver
James RE, Bekier ME, Lee P, Schroeder FA, Evans LJ, Wagner FF, et al. A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia. Brain. 2025. doi:10.1093/brain/awaf380. PMID: 41061670.
BibTeX
@article{james2025-41061670,
author = {James, Rebecca E. and Bekier, Michael E. and Lee, P. and Schroeder, Frederick A. and Evans, Lauren Jayne and Wagner, Florence F. and Hickman, Dean and Richardson, Tom and others},
title = {{A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia}},
journal = {Brain},
year = {2025},
doi = {10.1093/brain/awaf380},
pmid = {41061670},
url = {https://doi.org/10.1093/brain/awaf380}
}
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