AI-Assisted Discovery and Optimization of Small-Molecule TREM2 Agonists with Functional Microglial Activity

Cho, Sungwoo and Szalai, Tibor Viktor and El Gaamouch, Farida and Bajusz, Dávid and Keserű, György Miklós and Gabr, Moustafa (2026) AI-Assisted Discovery and Optimization of Small-Molecule TREM2 Agonists with Functional Microglial Activity. ACS MEDICINAL CHEMISTRY LETTERS, 17 (2). pp. 366-373. ISSN 1948-5875

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Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor whose loss-of-function variants increase Alzheimer’s disease (AD) risk. While antibody-based agonists have shown promise, their translation is hindered by poor brain penetration and high cost. Here, we report the discovery and optimization of small-molecule TREM2 agonists through an AI-assisted virtual screening strategy. Deep docking of over five million purchasable compounds identified a structurally novel hit, T2K-014, which engaged TREM2 with modest affinity. A SAR-by-catalog campaign led to the identification of T2M-010 as a potent binder. T2M-010 demonstrated favorable in vitro PK properties, including high solubility, passive BBB permeability, moderate metabolic stability, and minimal safety liabilities. Functionally, T2M-010 activated receptor-proximal signaling, inducing SYK phosphorylation in TREM2-expressing cells, and promoted microglial phagocytosis. Together, these findings establish T2M-010 as the most potent small-molecule TREM2 binder reported to date capable of driving protective microglial responses relevant to AD.

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