Discovery of an Achiral Small Molecule TREM2 Agonist with Improved Pharmacokinetic Profile and Validated Target Engagement

ABSTRACT The triggering receptor expressed on myeloid cells 2 (TREM2) is a lipid-sensing immunoreceptor on microglia that has emerged as a therapeutic target for Alzheimer’s disease. Here, we report the discovery of C1, an achiral structural analog of VG-3927—the first small molecule TREM2 agonist to enter clinical development. C1 was synthesized via a modular and enantioselective-free route using sequential Suzuki couplings, enabling rapid scaffold diversification. Compared to VG-3927, the stereochemically simplified derivative (C1) exhibits superior microglial phagocytosis and validated target engagement. C1 induces TREM2 activation in HEK293-hTREM2/DAP12 cells, and its direct binding to TREM2 was confirmed using both microscale thermophoresis (MST) and surface plasmon resonance (SPR). Importantly, C1 also demonstrates a superior pharmacokinetic profile to VG-3927, including enhanced metabolic stability in human and mouse microsomes, favorable PAMPA permeability, and a LogD7.4 compatible with CNS penetration. Docking studies suggested a potential binding mode of C1 at the extracellular domain of TREM2, revealing key polar and hydrophobic interactions. These findings position C1 as a synthetically accessible and pharmacokinetically favorable lead for the development of TREM2-targeted therapies Competing Interest Statement The authors have declared no competing interest. ABBREVIATIONS - Aβ - amyloid-beta - AD - Alzheimer’s disease - ADME - absorption, distribution, metabolism, excretion - BBB - blood–brain barrier - BPin - boronic acid pinacol ester - CNS - central nervous system - HEK293 - human embryonic kidney 293 cells - ITAM - immunoreceptor tyrosine-based activation motif - KD - equilibrium dissociation constant - MD - molecular dynamics - MMGBSA - molecular mechanics generalized Born surface area - MST - microscale thermophoresis - PAMPA - Parallel Artificial Membrane Permeability Assay - PK - pharmacokinetics - RMSD - root mean square deviation - SAR - structure–activity relationship - SPR - surface plasmon resonance - TREM2 - triggering receptor expressed on myeloid cells 2 - TPSA - topological polar surface area - TYROBP - TYRO protein tyrosine kinase binding protein.