# cGAS inhibitors for Alzheimer's disease treatment

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $847,498

## Abstract

ABSTRACT
Alzheimer's disease (AD) is the most common form of dementia in elderly. Amyloid-β (Aβ) and tau pathologies
and neuroinflammation are three major hallmarks of Alzheimer's disease. Vast majority of the drug discovery
efforts in the past decades have focused on targeting the Aβ pathology, but none are successful in Clinical Trials.
While tau pathology, not the Aβ pathology, has emerged to play critical role in memory decline in AD, drugs
targeting the direct effects of tau on neurons also have not met success either. Compelling human genetic studies
link the innate immune responses to elevated risk of developing late-onset AD, supporting targeting microglia,
resident immune cells in the brain, as the next-generation treatment for AD. We showed that a critical role of
cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) signaling in microglial toxicity and
tau-mediated cognitive decline. Activation of cGAS, a major cytosolic dsDNA sensor, catalyzes production of
cGAMP, an extremely potent STING agonist as the second messenger that activates cGAS-STING pathway,
leading to a production of the antiviral responses through activation of interferon regulatory factors (IRFs) and
expression of cytokine and type I interferon genes. We found that a partial or complete genetic cGAS ablation
protected against the tau-mediated spatial learning and memory deficits in PS19 Tau mice. Moreover, treatment
with a small molecule inhibitor of cGAS reduces interferon responses, diminished microgliosis, and protected
against cognitive deficits in an AD mouse model with tauopathy. We hypothesize that inhibitors the cGAS activity
will dampen neuroinflammation and maladaptive immune responses, protect against AD-related deficit. We
propose to develop small molecule human cGAS (h-cGAS) inhibitors as novel microglial modulators to treat AD.
In Aim 1, we will develop lead h-cGAS inhibitors starting with two known hits and determine whether these
inhibitors effectively modulate the cGAS-STING pathway in cell-free and cell-based assays. We expect to identify
new hits via hits expansion and synthesize >200 analogs. Aim 2 focuses on optimization of analogs a potent
cGAS inhibitor, TDI-6570, which is a lead low nanomolar potent mouse cGAS (m-cGAS) inhibitor and possesses
10x less h-cGAS activity. We will design up to 50 new analogs. Results of SAR, docking experiments, and in-
silico calculation will be used to maximize the lead quality. Completion of Aim 1 and Aim 2 will lead to 5 lead
compounds for in vivo and efficacy studies. In Aim 3, we will establish PK and efficacy of h-cGAS inhibitors in
mouse model of tauopathy, and efficacy in human stem cell-derived microglia and cerebral organoids with
tauopathy. At the end of the proposed 5 years study, we anticipate identifying 1-2 lead h-cGAS inhibitors as tool
compounds and a proof of principle to further advance as drug candidates to treat Alzheimer's disease and
related neurological disorders.

## Key facts

- **NIH application ID:** 10457004
- **Project number:** 5R01AG074541-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Li Gan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $847,498
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457004

## Citation

> US National Institutes of Health, RePORTER application 10457004, cGAS inhibitors for Alzheimer's disease treatment (5R01AG074541-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10457004. Licensed CC0.

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