Discovery of a Small Molecule TREM2 Agonist with Improved In Vitro Pharmacokinetic Profile and Validated Target Engagement

  • ACS Med Chem Lett. 2025 Jul 29;16(8):1634-1640. doi: 10.1021/acsmedchemlett.5c00299.
Shaoren Yuan  1 ,  Farida El Gaamouch  1 ,  Sungwoo Cho  1 ,  Katarzyna Kuncewicz  1  2 ,  Hossam Nada  1 ,  Moustafa T Gabr  1
Affiliations
  • 1. Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, New York 10065, United States.
  • 2. Department of Biomedical Chemistry, Faculty of Chemistry, University of Gdansk, Gdansk 80-309, Poland.
PMID: 40832531 DOI: 10.1021/acsmedchemlett.5c00299
Abstract

The microglial lipid-sensing receptor TREM2 is a promising therapeutic target for Alzheimer's disease. We report the discovery of C1, a racemic structural analog of the clinical-stage TREM2 agonist VG-3927. Synthesized via a concise, modular, and enantioselective-free route using sequential Suzuki couplings, C1 enables rapid scaffold diversification. Compared to VG-3927, this stereochemically simplified derivative exhibits superior microglial phagocytosis and activates TREM2 signaling in HEK293-hTREM2/DAP12 cells, demonstrating validated target engagement. Direct binding of C1 to TREM2 was unequivocally confirmed by both surface plasmon resonance (SPR) and microscale thermophoresis (MST). Critically, C1 displays a superior in vitro pharmacokinetic profile to VG-3927: enhanced metabolic stability in human and mouse liver microsomes, favorable passive permeability (PAMPA), and a CNS-compatible log D7.4. Docking studies suggest a potential binding mode for C1 within TREM2's extracellular domain, revealing key interactions. These attributes establish C1 as an accessible and pharmacokinetically favorable lead compound with strong potential for developing TREM2-targeted therapies.

Keywords
Alzheimer’s disease; TREM2; computational chemistry; drug discovery; pharmacokinetics.
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