Novel Small-Molecule Analogues of IU1 Ameliorate Amyloid-β Mediated Toxicity in Alzheimer's Disease Cell and Worm Models.

Ajish Ariyath^1,2, Fraulein Denise Arigo^1,2, Izhar Wallach³, W M A D Binosha Fernando^1,2, Ralph N Martins^1,2,4, Prashant Bharadwaj^1,2,5

¹Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical and Health Sciences, Sarich and Patricia Neuroscience Research Institute, Edith Cowan University, Joondalup, WA 6027, Australia.

²Alzheimer's Research Australia, Nedlands, WA 6009, Australia.

³Atomwise, 250 Sutter St, Suite 650, San Francisco, CA 94108, USA.

⁴School of Biomedical Science, Macquarie University, Sydney, NSW 2109, Australia.

⁵Curtin Medical School, Curtin Health and Innovation Research Institute (CHIRI), Faculty of Health Sciences, Curtin University, Perth, WA 6107, Australia.

PubMed PMC DOI PDF

Abstract

Dysregulation of the deubiquitinating enzyme Ubiquitin-specific peptidase 14 (USP14) is implicated in several neurodegenerative diseases, and IU1, an allosteric inhibitor, has shown neuroprotective effects by reducing protein aggregate toxicity. This study aimed to develop new IU1 analogues and evaluate their ability to mitigate amyloid-β (Aβ) accumulation and toxicity in Alzheimer's disease (AD)…

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Mentioned Companies

Atomwise
affiliation

Other Funding

National Health and Medical Research Council(APP1107109)
National Foundation for Medical Research and Innovation(NA)

MeSH Terms

Animals0Caenorhabditis elegans0Alzheimer Disease*Amyloid beta-Peptides*Humans0Disease Models, Animal0Neuroprotective Agents*Clioquinol*Small Molecule Libraries*Proteasome Endopeptidase Complex0

Keywords

amyloid precursor proteinamyloid-β proteinartificial intelligencedeubiquitinase enzymeubiquitin–proteasome system

Article Info

PMID: 41752099
PMCID: PMC12940727
DOI: 10.3390/ijms27041963
Received: January 16, 2026
Accepted: February 14, 2026

How to Cite

Ariyath A et al. Novel Small-Molecule Analogues of IU1 Ameliorate Amyloid-β Mediated Toxicity in Alzheimer's Disease Cell and Worm Models. Int J Mol Sci2026;27(4) doi:10.3390/ijms27041963

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