# Novel Inhibitors of Lysine Methyltransferases G9a and GLP for the Treatment of Alzheimer's Disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $661,299

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD), the most prevalent dementia, has no effective disease-modifying therapeutics. Our
recent studies have linked abnormalities in lysine methyltransferases G9a/GLP (also known as EHMT2/1) and
histone H3 lysine 9 dimethylation (H3K9me2) to AD pathophysiology. We hypothesize that pharmacological
inhibition of G9a and GLP by small molecules can provide a novel and effective therapeutic strategy for the
treatment of AD. The objectives of this project are: (a) to demonstrate that newly-discovered G9a/GLP inhibitors
are efficacious in AD mouse models; (b) to optimize small-molecule inhibitors of G9a and GLP into a drug
candidate. To achieve these goals, we will pursue three specific aims. Aim 1, assess selectivity, cellular activity
and in vitro ADME (absorption, distribution, metabolism and excretion) and in vivo pharmacokinetic (PK)
properties of lead G9a/GLP inhibitors; Aim 2, evaluate in vivo effects of lead G9a/GLP inhibitors on
normalizing behavioral, synaptic, and transcriptional abnormalities in AD mouse models; Aim 3, Optimize
current G9a/GLP inhibitor leads into a drug candidate by designing, synthesizing and testing novel compounds
to simultaneously optimize potency, selectivity and PK properties. Completion of the proposed studies will not
only validate our therapeutic hypothesis, but also generate a drug candidate that could be ultimately translated
in the clinic for the treatment of AD. The improved G9a/GLP inhibitors generated in this project will also be
invaluable chemical tools for assessing the therapeutic potential of G9a/GLP inhibition in other diseases.

## Key facts

- **NIH application ID:** 10922848
- **Project number:** 5R01AG084184-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Jian Jin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $661,299
- **Award type:** 5
- **Project period:** 2023-09-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10922848

## Citation

> US National Institutes of Health, RePORTER application 10922848, Novel Inhibitors of Lysine Methyltransferases G9a and GLP for the Treatment of Alzheimer's Disease (5R01AG084184-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10922848. Licensed CC0.

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