Discovery of first-in-class small molecule TREM2 ligands as therapeutics for Alzheimer's disease

PROJECT SUMMARY/ABSTRACT: Microglial-mediated neuroinflammation has long been recognized as a pathological hallmark of the progression of Alzheimer's disease (AD). Although many anti-inflammatory drug candidates have undergone clinical trials as potential AD therapeutics, most have failed. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor that mediates intracellular cascades to modulate the production of inflammatory cytokines and the phagocytosis of amyloid  (A) plaques. The interaction of TREM2 with galectin-3 (Gal-3) stimulates proinflammatory activation of microglia and represents a promising target for developing AD therapeutics that can alleviate neuroinflammation. In addition, stabilizing TREM2/A interaction has been reported to enhance TREM2-mediated A phagocytosis in vivo. However, targeting TREM2 is currently restricted to antibodies (Abs), and there are no small molecules in existence that target TREM2. To fill this gap, we have developed an innovative platform, Small Molecules from Antibody Pharmacophores (SMAPs), that can identify small molecule ligands for immune cell receptors with high binding affinity and selectivity. Our SMAPs platform is based on utilizing cocrystal structures of immune cell receptors with Abs in building pharmacophore maps from clusters of key interacting residues of Abs with immune cell receptors to identify small molecules that modulate the function of immune cell receptors. We propose to establish a new microglial modulating strategy to treat AD based on therapeutic targeting of TREM2 with small molecules identified from the SMAPs platform. We identified a focused chemical library using our pharmacophore-based virtual screening approach (SMAPs) based on interactions derived from a cocrystal structure of TREM2 and anti-TREM2 Ab single-chain variable fragment (scFv) (PDB ID: 6Y6C). In comparison to Abs, small molecules can readily cross the blood-brain barrier (BBB) and are amenable to pharmacokinetic optimization, which may enable avoiding immune-related adverse events associated with Abs. Building on our successful work in establishing screening platforms for TREM2-targeted small molecules, we hypothesize that small molecules can bind a novel druggable binding site in TREM2, consequently enabling therapeutic modulation of TREM2 interaction with both Gal-3 and A. We will test our hypothesis and attain our objective via the following specific aims: (1) screening the focused chemical using a panel of cell-free and cell-based assays, followed by hit-to- lead optimization, and (2) evaluation of the optimized leads in an AD mouse model following an assessment of their pharmacokinetic (PK) profiles. This research will lay the groundwork for the therapeutic modulation of TREM2 function using small molecules to develop new AD therapeutics.