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

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, <b>T2K-014</b>, which engaged TREM2 with modest affinity. A SAR-by-catalog campaign led to the identification of <b>T2M-010</b> as a potent binder. <b>T2M-010</b> demonstrated favorable in vitro PK properties, including high solubility, passive BBB permeability, moderate metabolic stability, and minimal safety liabilities. Functionally, <b>T2M-010</b> activated receptor-proximal signaling, inducing SYK phosphorylation in TREM2-expressing cells, and promoted microglial phagocytosis. Together, these findings establish <b>T2M-010</b> as the most potent small-molecule TREM2 binder reported to date capable of driving protective microglial responses relevant to AD.