ArticleAlzheimer's & dementia (New York, N. Y.)
Baricitinib and tofacitinib off-target profile, with a focus on Alzheimer's disease.
Article in Alzheimer's & dementia (New York, N. Y.). The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 11 citations in OpenAlex.
- Immunotherapies for risk reduction in age-associated neurodegenerative diseases: impact of sex and treatment duration.medRxiv : the preprint server for health sciences · 2026Article
- JAK/STAT signaling pathway inhibitors in neurodegenerative diseases: current status and future perspectives.Frontiers in aging neuroscience · 2026Review
- Neuroinflammation and Disease: Pathways and Opportunities.Annual review of pharmacology and toxicology · 2026Review
- Anti-inflammatory and immunomodulatory therapies are associated with reduced risk of age-associated neurodegenerative diseases: impact of sex and treatment duration.Frontiers in aging neuroscience · 2026Article
- From Genome-Wide SNPs to Neuroimmune Crosstalk: Mapping the Genetic Landscape of IBD and Its Brain Overlap.Biology · 2025Article
- Proteogenomic signature of Alzheimer's disease and related dementia risk in individuals with major depressive disorder.Nature. Mental health · 2025Article
- The Crucial Role of the Blood-Brain Barrier in Neurodegenerative Diseases: Mechanisms of Disruption and Therapeutic Implications.Journal of clinical medicine · 2025Review
- Neurodegenerative diseases and neuroinflammation-induced apoptosis.Open life sciences · 2025Review
- Common cytokine receptor gamma chain family cytokines activate MAPK, PI3K, and JAK/STAT pathways in microglia to influence Alzheimer's Disease.Frontiers in molecular neuroscience · 2024Article
- Baricitinib and tofacitinib off-target profile, with a focus on Alzheimer's disease.Alzheimer's & dementia (New York, N. Y.)Article
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionJanus kinase (JAK) inhibitors were recently identified as promising drug candidates for repurposing in Alzheimer's disease (AD) due to their capacity to suppress inflammation via modulation of JAK/STAT signaling pathways. Besides interaction with primary therapeutic targets, JAK inhibitor drugs frequently interact with unintended, often unknown, biological off-targets, leading to associated effects. Nevertheless, the relevance of JAK inhibitors' off-target interactions in the context of AD remains unclear.
methodsPutative off-targets of baricitinib and tofacitinib were predicted using a machine learning (ML) approach. After screening scientific literature, off-targets were filtered based on their relevance to AD. Targets that had not been previously identified as off-targets of baricitinib or tofacitinib were subsequently tested using biochemical or cell-based assays. From those, active concentrations were compared to bioavailable concentrations in the brain predicted by physiologically based pharmacokinetic (PBPK) modeling.
resultsWith the aid of ML and in vitro activity assays, we identified two enzymes previously unknown to be inhibited by baricitinib, namely casein kinase 2 subunit alpha 2 (CK2-α2) and dual leucine zipper kinase (MAP3K12), both with binding constant (
conclusionIn this study, we extended the list of baricitinib off-targets that are potentially relevant for AD progression and predicted drug distribution in the brain. The results suggest a low likelihood of successful repurposing in AD due to low brain permeability, even at the maximum recommended daily dose. While additional research is needed to evaluate the potential impact of the off-target interaction on AD, the combined approach of ML-based target prediction, in vitro confirmation, and PBPK modeling may help prioritize drugs with a high likelihood of being effectively repurposed for AD. Highlights: This study explored JAK inhibitors' off-targets in AD using a multidisciplinary approach.We combined machine learning, in vitro tests, and PBPK modelling to predict and validate new off-target interactions of tofacitinib and baricitinib in AD.Previously unknown inhibition of two enzymes (CK2-a2 and MAP3K12) by baricitinib were confirmed using in vitro experiments.Our PBPK model indicates that baricitinib low brain permeability limits AD repurposing.The proposed multidisciplinary approach optimizes drug repurposing efforts in AD research.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.