TREM2 Activation by First-in-Class Direct Small Molecule Agonists: DEL Screening, Optimization, Biophysical Validation, and Functional Characterization

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial function, and its loss-of-function variants are linked to Alzheimers disease (AD) and neurodegenerative disorders. While TREM2 activation is a promising therapeutic strategy, no small molecule agonists acting via direct TREM2 binding have been reported to date. Here, we describe the discovery of first-in-class, direct small molecule TREM2 agonists identified through DNA-encoded library (DEL) screening. The DEL hit (4a) demonstrated TREM2 binding affinity, as validated by three biophysical screening platforms (TRIC, MST, and SPR), induced Syk phosphorylation, and enhanced microglial phagocytosis. Preliminary optimization yielded 4i, which maintained TREM2 engagement with improved selectivity over TREM1 and no cytotoxicity. Molecular dynamics simulations revealed that 4a stabilizes a transient binding pocket on TREM2, suggesting a novel mechanism for receptor activation. These findings provide the first proof-of-concept for direct pharmacological TREM2 agonism, offering a foundation for developing therapeutics against AD and related disorders. Table of Contents graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/655617v1_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@14a3d24org.highwire.dtl.DTLVardef@f423deorg.highwire.dtl.DTLVardef@5ee108org.highwire.dtl.DTLVardef@107e6df_HPS_FORMAT_FIGEXP M_FIG C_FIG