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

Area of Science:

• Neuroscience
• Pharmacology
• Immunology

Background:

• Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial for microglial function and its dysfunction is linked to increased Alzheimer's disease (AD) risk.
• Current TREM2 agonists (antibodies) face challenges with brain penetration and cost, limiting their therapeutic potential for AD.

Purpose of the Study:

• To discover and optimize novel small-molecule agonists targeting TREM2 for potential AD treatment.
• To identify a potent and brain-penetrant small molecule that can modulate microglial activity.

Main Methods:

• Utilized AI-assisted virtual screening and deep docking of over five million compounds to identify initial TREM2 binders.
• Employed a Structure-Activity Relationship (SAR)-by-catalog approach for hit optimization.
• Evaluated in vitro pharmacokinetic (PK) properties, including solubility, blood-brain barrier (BBB) permeability, and metabolic stability.
• Assessed functional activity, including receptor-proximal signaling (SYK phosphorylation) and microglial phagocytosis.

Main Results:

• Identified T2K-014 as an initial hit, followed by optimization to T2M-010, a potent TREM2 binder.
• T2M-010 exhibited favorable in vitro PK properties: high solubility, passive BBB permeability, and moderate metabolic stability.
• T2M-010 demonstrated functional efficacy by activating TREM2 signaling and enhancing microglial phagocytosis in vitro.

Conclusions:

• T2M-010 represents the most potent small-molecule TREM2 agonist reported to date.
• This novel compound has the potential to drive protective microglial responses relevant to Alzheimer's disease pathogenesis.
• Small-molecule TREM2 agonists offer a promising therapeutic avenue for AD, overcoming limitations of antibody-based approaches.