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

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-07-29 DOI:10.1021/acsmedchemlett.5c00299

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

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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.

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一种小分子TREM2激动剂的发现，具有改善的体外药代动力学特征和有效的靶标结合

小胶质脂敏感受体TREM2是阿尔茨海默病的一个有希望的治疗靶点。我们报告了C1的发现，C1是临床阶段TREM2激动剂VG-3927的外消旋结构类似物。C1通过简洁、模块化和无对映体选择性的路线合成，使用顺序铃木偶联，使支架快速多样化。与ug -3927相比，该立体化学简化衍生物表现出优越的小胶质细胞吞噬能力，并激活HEK293-hTREM2/DAP12细胞中的TREM2信号，证明了有效的靶向作用。表面等离子体共振（SPR）和微尺度热泳（MST）明确证实了C1与TREM2的直接结合。重要的是，C1比VG-3927表现出更好的体外药代动力学特征：增强了人和小鼠肝微粒体的代谢稳定性，有利的被动通透性（PAMPA），以及cns兼容的日志D7.4。对接研究表明，C1在TREM2的细胞外结构域中存在潜在的结合模式，揭示了关键的相互作用。这些特性使C1成为一种易于获取且药代动力学有利的先导化合物，具有开发trem2靶向治疗的强大潜力。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.