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Pharmacology & ToxicologyACS Medicinal Chemistry Letters
Peer-reviewed journal article

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

S. Cho, Tibor Viktor SzalaiiD, Farida El Gaamouch, Dávid BajusziD, György Miklós KeserűiD, Moustafa Tarek GabriD

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor whose loss-of-function variants increase Alzheimers disease (AD) risk by impairing plaque compaction, survival, and protective microglial programming. 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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In-depth summary

✦ Multi-agent verified full-text synthesis

Claude Opus 5.5 · xhigh effort · 5 Nov 2026 · from the full text of version 1 (17 Sept 2025)

Deep Docking virtual screening of over five million compounds and structure-activity optimization yielded T2M-010, a submicromolar small-molecule TREM2 agonist that induces SYK phosphorylation and microglial phagocytosis.

Loss-of-function variants in the microglial receptor TREM2 increase Alzheimer's disease risk, but antibody agonists face poor blood-brain barrier penetration and high manufacturing costs. Discovering brain-penetrant small-molecule TREM2 agonists provides an orally bioavailable chemical scaffold beyond the single previously reported chemotype (VG-3927).

Key results

  1. ShownAI-assisted Deep Docking virtual screening identified T2K-014 as a structurally distinct small-molecule binder of human TREM2.

    Screening >5 million purchasable compounds against the Hecubine pocket of TREM2 and testing the top 30 hits at 100 μM against 10 nM recombinant human TREM2 via TRIC and MST identified T2K-014 (Kd = 28.88 ± 1.74 μM, 0.099 Morgan fingerprint Tanimoto similarity to Hecubine). · Abstract; Abstract; Figure legends

  2. ShownSAR-by-catalog optimization around the T2K-014 scaffold improved TREM2 binding affinity 35-fold to submicromolar potency in T2M-010.

    Testing 27 commercial analogs across the R1 indole and R2 pyridine positions by TRIC (100 μM) and MST (n = 3) yielded four hits that all conserved the R1 indole: T2M-010 (Kd = 0.83 ± 0.10 μM, 35-fold improvement), T2M-003 (Kd = 1.35 ± 0.16 μM, 21-fold), T2M-016 (Kd = 2.44 ± 0.30 μM, 12-fold), and T2M-002 (Kd = 50.84 ± 3.74 μM). · Abstract; Figure legends; Tables

  3. ShownT2M-010 activates proximal TREM2-DAP12 signaling and stimulates microglial phagocytosis to levels comparable to benchmark agonist VG-3927.

    At 25 μM, T2M-010 induced a twofold increase in SYK phosphorylation (Tyr525/526) in HEK-hTREM2/DAP12 cells (n = 5 biological replicates) and significantly increased fluorescent bead uptake in IBA1-positive BV2 microglial cells (n = 4 biological replicates, 32 images/group, p < 0.0001), whereas analog T2M-016 produced no significant phospho-SYK increase. · Abstract; Figure legends

  4. ShownIn vitro ADME/PK and safety counterscreens support the central nervous system drug-likeness of T2M-010.

    T2M-010 showed logD7.4 = 2.8, PBS solubility of 48 μM (FaSSIF 95 μM), PAMPA-BBB Pe = 9.2 x 10^-6 cm/s, MDCK-MDR1 Papp = 2.85 x 10^-5 cm/s (efflux ratio 1.07), plasma half-lives of 167 min (mouse) and 214 min (human), microsomal half-lives of 51.6 ± 2.2 min (mouse) and 68.4 ± 3.1 min (human), fibroblast IC50 > 100 μM, hERG IC50 > 60 μM, and CYP inhibition <= 11.2% at 10 μM. · Abstract; Tables

Methods, data and reproducibility

Screened >5 million purchasable compounds against the human TREM2 Hecubine pocket via Deep Docking and tested 30 virtual hits plus 27 T2K-014 SAR-by-catalog analogs against 10 nM recombinant human TREM2 using TRIC (100 μM) and MST. Assayed cellular TREM2 activation at 25 μM via AlphaLISA phospho-SYK in HEK-hTREM2/DAP12 cells and bead uptake in BV2 microglia, plus in vitro ADME/PK profiling.

  • Purchasable small-molecule library (>5 million compounds), top 30 virtual hits, and 27 commercial SAR analogs assayed against recombinant human TREM2 · human · n = 30 virtual hits and 27 SAR derivatives (n = 3 MST replicates)
  • Cellular signaling (HEK-hTREM2/DAP12), phagocytosis (BV2 microglia), permeability (MDCK-MDR1), cytotoxicity (WI-38, HS-27 fibroblasts), and mouse/human plasma and liver microsome assays · human, mouse · n = 5 biological replicates (phospho-SYK); 4 biological replicates, 32 images/group
Methods & tools
Deep Docking, Dianthus (TRIC), Microscale Thermophoresis (MST), AlphaLISA SureFire Ultra
Reproducibility gaps
Computational docking workflows, compound vendor catalog identifiers, and experimental assay protocols are placed in external Supporting Information PDF without public code or data links.
Limitations (2)
  • Structure-activity relationship conclusions rely on a small catalog set of 27 derivatives around T2K-014, several of which caused aggregation or fluorescence interference during primary TRIC screening. · stated by the authors
  • All target engagement, microglial functional, and pharmacokinetic data are strictly in vitro, requiring further medicinal chemistry optimization and in vivo validation in Alzheimer's disease animal models. · stated by the authors

Who should read:Read this if you work on structure-based virtual screening, small-molecule TREM2 agonists, or neuroimmune drug discovery for Alzheimer's disease.

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