# Development of DYRK1A allosteric modulator for the treatment of Alzheimer's Disease

> **NIH NIH SB1** · AVANTI BIOSCIENCES, INC. · 2024 · $1,134,429

## Abstract

PROJECT SUMMARY
 This proposal aims to develop ABI-171, a potent and selective inhibitor of the “Dual-specificity tyrosine-
(Y)-phosphorylation Regulated Kinase-1A” (DYRK1A), to treat mild to moderate Alzheimer’s disease (AD)
because of its role in inflammation and phosphorylation of key target protein like Amyloid Precursor Protein
(APP), Presenilin-1 (PS1), and tau.
 AD is a neurodegenerative disorder is characterized by neuronal death and loss of gray matter in the
frontal cortex and hippocampus. Memory loss is a typical symptom of AD and has been linked to the
accumulation of amyloid plaques and neurofibrillary tangles (NFTs). A compelling body of data points to
hyperphosphorylated tau species as mediators of toxicity in AD; they participate in forming NFTs whose
presence is closely linked with disease progression. According to the β-amyloid cascade hypothesis, the
deposition of insoluble β-amyloid is responsible for neuronal death. Plaques are constituted by β-amyloid
peptides (Aβ) that are generated via the cleavage of the amyloid precursor protein (APP) by β- and γ-secretases.
 DYRK1A is a proline-directed serine/threonine kinase for which many proteins are shown as substrate1.
DYRK1A activity may be involved in AD pathogenesis because (1) it is robustly expressed in CNS neurons; (2)
directly attenuate inflammation by targeting Nrf2 and GFAP; (3) DYRK1A phosphorylates APP directly and
increases the secretase-mediated cleavage of APP into Aβ peptides; (4) DYRK1A is a kinase for which tau
serves as a substrate and its presence is associated with increased phosphorylation of tau; (5) DYRK1A selective
inhibitor ABI-171 is efficacious in a pilot 5xFAD efficacy model, an AD animal model. Significantly, DYRK1A
primes tau for additional phosphorylation by GSK3β kinase, which is known to contribute to AD pathogenesis.
(6) DYRK1A phosphorylates PS1 a subunit of γ-secretase, and this phosphorylation event increases γ-secretase
protease activity, further elevating Aβ peptide production. These findings support our hypothesis that inhibition
of DYRK1A activity will be disease-modifying and significantly impact the lives of those with AD.
 Despite a role for DYRK1A in AD pathogenesis, few pharmaceutical industry efforts target the modulation
of this enzyme. Avanti Biosciences is specifically and uniquely focused on discovering negative modulators
selectively of DYRK1A in the brain. This Commercialization Readiness Pilot (CRP) grant will allow us to continue
the work from the original grant 1R44AG056181 and enable us to confirm the efficacy of the drug in the treatment
of AD, study in more detail its mechanism of action, complete the CMC and safety studies that are necessary to
file an IND with the FDA.
 In this grant, four specific aims (SA) are proposed: in SA1 we propose studying the molecule in a chronic
model of AD in which the mechanism of action is explored. In SA2 we investigate the toxicity of the drug and
 determine its therapeutic index. In SA ...

## Key facts

- **NIH application ID:** 10892165
- **Project number:** 5SB1AG056181-06
- **Recipient organization:** AVANTI BIOSCIENCES, INC.
- **Principal Investigator:** Gian Luca Araldi
- **Activity code:** SB1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,134,429
- **Award type:** 5
- **Project period:** 2017-08-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892165

## Citation

> US National Institutes of Health, RePORTER application 10892165, Development of DYRK1A allosteric modulator for the treatment of Alzheimer's Disease (5SB1AG056181-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10892165. Licensed CC0.

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