# Small molecule inhibitors of CAPON-induced tau aggregation

> **NIH NIH RF1** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $1,980,378

## Abstract

PROJECT SUMMARY/ABSTRACT:
 Alzheimer's disease (AD), the most common type of dementia worldwide, is a rapidly increasing public
health concern. There is an urgent need for the validation of novel targets and therapeutic strategies for AD.
Given the heterogeneity of AD pathogenesis, targeting the connection between amyloid pathology, tau
pathology, and neuronal cell death in AD is gaining increasing interest as a therapeutic strategy for AD. In this
context, CAPON (the carboxy-terminal PDZ ligand of neuronal nitric oxide synthase (nNOS)) has been recently
identified as a novel tau-binding protein that represents a promising target to break the connection between
amyloid beta (Aβ), tau, and neurodegeneration. In tauopathy models, CAPON/tau interaction induces tau
aggregation and neurodegeneration, while CAPON deficiency ameliorates AD-related pathological
phenotypes. Moreover, the interaction between CAPON and nNOS mediates A-induced neurotoxicity in AD
animal models. However, there are no small molecules reported to date that target the multifaceted role of
CAPON in AD pathogenesis. Our goal is to establish targeting CAPON with small molecules as a promising
therapeutic strategy for AD. Our hypothesis is that CAPON-targeted small molecules with dual inhibition of
CAPON/tau and CAPON/nNOS interactions can ameliorate neuronal cell death and tau pathology. Building on
our previous work focused on the discovery of small molecule modulators of tau and amyloid aggregation, we
propose to screen a central nervous system (CNS)-focused chemical library of small molecules for the ability to
bind CAPON using a temperature-related intensity change (TRIC)-based assay. Subsequently, we will use
time-resolved fluorescence energy transfer (TR-FRET) assays to identify small molecule CAPON binders that
inhibit CAPON-centered interactions (Aim 1). We will validate the identified hits using a panel of screening
assays for CAPON-targeted small molecules and perform structural optimization guided by molecular modeling
and site-directed mutagenesis (Aim 2). In Aims 2 and 3, we propose to evaluate the therapeutic potential of the
optimized leads using a combination of in vitro assays and two AD mouse models. The selection of three leads
for the AD mouse models will be guided by the assessment of the pharmacokinetic (PK) profiles and in vivo
target engagement of the investigated compounds. The proximal expected outcome of this work is validating
the potential of small molecules to target CAPON and efficiently block CAPON/tau and CAPON/nNOS
interactions in vivo. The optimized leads from this work will serve as the basis for future target-based drug
development programs and preclinical AD studies.

## Key facts

- **NIH application ID:** 10979242
- **Project number:** 1RF1AG084635-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Moustafa Gabr
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,980,378
- **Award type:** 1
- **Project period:** 2024-08-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979242

## Citation

> US National Institutes of Health, RePORTER application 10979242, Small molecule inhibitors of CAPON-induced tau aggregation (1RF1AG084635-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10979242. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*