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

Shaoren Yuan; Farida El Gaamouch; Sungwoo Cho; Katarzyna Kuncewicz; Hossam Nada; Moustafa T. Gabr

doi:10.1021/acsmedchemlett.5c00299

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

Shaoren Yuan
, Farida El Gaamouch
, Sungwoo Cho
, Katarzyna Kuncewicz
, Hossam Nada
, Moustafa T. Gabr

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English
Pages (from-to)	1634-1640
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	16
Issue number	8
DOIs	https://doi.org/10.1021/acsmedchemlett.5c00299
State	Published - 14 Aug 2025
Externally published	Yes

Keywords

Alzheimer’s disease
TREM2
computational chemistry
drug discovery
pharmacokinetics

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10.1021/acsmedchemlett.5c00299

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

abstract = "The microglial lipid-sensing receptor TREM2 is a promising therapeutic target for Alzheimer{\textquoteright}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{\textquoteright}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{\textquoteright}s disease, TREM2, computational chemistry, drug discovery, pharmacokinetics",

author = "Shaoren Yuan and \{El Gaamouch\}, Farida and Sungwoo Cho and Katarzyna Kuncewicz and Hossam Nada and Gabr, \{Moustafa T.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors. Published by American Chemical Society",

year = "2025",

month = aug,

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doi = "10.1021/acsmedchemlett.5c00299",

language = "English",

volume = "16",

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journal = "ACS Medicinal Chemistry Letters",

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T1 - Discovery of a Small Molecule TREM2 Agonist with Improved In Vitro Pharmacokinetic Profile and Validated Target Engagement

AU - Yuan, Shaoren

AU - El Gaamouch, Farida

AU - Cho, Sungwoo

AU - Kuncewicz, Katarzyna

AU - Nada, Hossam

AU - Gabr, Moustafa T.

PY - 2025/8/14

Y1 - 2025/8/14

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - TREM2

KW - computational chemistry

KW - drug discovery

KW - pharmacokinetics

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DO - 10.1021/acsmedchemlett.5c00299

M3 - Article

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SN - 1948-5875

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JF - ACS Medicinal Chemistry Letters

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ER -

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

Abstract

Keywords

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