# Discovery of first-in-class small molecule TREM2 ligands as therapeutics for Alzheimer's disease

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $768,267

## Abstract

PROJECT SUMMARY/ABSTRACT:
 Microglial-mediated neuroinflammation has long been recognized as a pathological hallmark of the
progression of Alzheimer's disease (AD). Although many anti-inflammatory drug candidates have undergone
clinical trials as potential AD therapeutics, most have failed. Triggering receptor expressed on myeloid cells 2
(TREM2) is a microglia-specific receptor that mediates intracellular cascades to modulate the production of
inflammatory cytokines and the phagocytosis of amyloid  (A) plaques. The interaction of TREM2 with
galectin-3 (Gal-3) stimulates proinflammatory activation of microglia and represents a promising target for
developing AD therapeutics that can alleviate neuroinflammation. In addition, stabilizing TREM2/A interaction
has been reported to enhance TREM2-mediated A phagocytosis in vivo. However, targeting TREM2 is
currently restricted to antibodies (Abs), and there are no small molecules in existence that target TREM2. To fill
this gap, we have developed an innovative platform, Small Molecules from Antibody Pharmacophores
(SMAPs), that can identify small molecule ligands for immune cell receptors with high binding affinity and
selectivity. Our SMAPs platform is based on utilizing cocrystal structures of immune cell receptors with Abs in
building pharmacophore maps from clusters of key interacting residues of Abs with immune cell receptors to
identify small molecules that modulate the function of immune cell receptors. We propose to establish a new
microglial modulating strategy to treat AD based on therapeutic targeting of TREM2 with small molecules
identified from the SMAPs platform. We identified a focused chemical library using our pharmacophore-based
virtual screening approach (SMAPs) based on interactions derived from a cocrystal structure of TREM2 and
anti-TREM2 Ab single-chain variable fragment (scFv) (PDB ID: 6Y6C). In comparison to Abs, small molecules
can readily cross the blood-brain barrier (BBB) and are amenable to pharmacokinetic optimization, which may
enable avoiding immune-related adverse events associated with Abs. Building on our successful work in
establishing screening platforms for TREM2-targeted small molecules, we hypothesize that small molecules
can bind a novel druggable binding site in TREM2, consequently enabling therapeutic modulation of TREM2
interaction with both Gal-3 and A. We will test our hypothesis and attain our objective via the following specific
aims: (1) screening the focused chemical using a panel of cell-free and cell-based assays, followed by hit-to-
lead optimization, and (2) evaluation of the optimized leads in an AD mouse model following an assessment of
their pharmacokinetic (PK) profiles. This research will lay the groundwork for the therapeutic modulation of
TREM2 function using small molecules to develop new AD therapeutics.

## Key facts

- **NIH application ID:** 10881021
- **Project number:** 1R01AG083512-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Moustafa Gabr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $768,267
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881021

## Citation

> US National Institutes of Health, RePORTER application 10881021, Discovery of first-in-class small molecule TREM2 ligands as therapeutics for Alzheimer's disease (1R01AG083512-01A1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10881021. Licensed CC0.

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