TY - JOUR
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.
N1 - Publisher Copyright:
© 2025 The Authors. Published by American Chemical Society
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
UR - https://www.scopus.com/pages/publications/105024667023
U2 - 10.1021/acsmedchemlett.5c00299
DO - 10.1021/acsmedchemlett.5c00299
M3 - Article
AN - SCOPUS:105024667023
SN - 1948-5875
VL - 16
SP - 1634
EP - 1640
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 8
ER -
