As48 is a selective TREM2 agonist with a K D value of 12.48 μM in TRIC binding assay. As48 binds near the TREM2 cleavage region, forms hydrogen bonds with Gly68, reduces conformational flexibility in regions 58-102, restricts protease accessibility to the cleavage site. As48 activates SYK phosphorylation, enhances microglial phagocytosis, and induces downstream calcium signaling in TREM2-expressing cells. As48 inhibits TREM2 ectodomain shedding without affecting ADAM10/17 protease activities. As48 can be used for the research of Alzheimer's disease [1].
In Vitro, As48 (0.1-1000 μM; 10 min) binds directly to recombinant human TREM2 protein with a K0 of 12.48 μM, as measured by TRIC binding assay[1]. As48 (0.01-100 μM; 10 min) binds to recombinant human TREM2 with a KD of 13.8 μM, and binds 7-fold more weakly to recombinant human TREM1 (KD = 97.92 μM), as measured by MST binding assay[1]. As48 (30 μM; 20 min) increases the thermal stability of recombinant human TREM2 protein by +3.86°C, as measured by thermal shift assay[1]. As48 (1.23-100 μM) binds directly to biotinylated recombinant human TREM2 protein with a KD of 29.5 μM, as measured by SPR binding assay[1]. As48 (0-300 μM; overnight) exhibits minimal cytotoxicity in HMC3 human microglial cells, with no significant viability loss at concentrations up to 100 μM, as measured by MTS assay[1]. As48 (5-100 μM; 5-60 min) activates TREM2 signaling in HEK293-hTREM2/DAP12 cells by inducing dose- and time-dependent SYK phosphorylation[1]. As48 (0.3-30 μM; 10 min) induces TREM2-dependent intracellular calcium mobilization in HEK293-hTREM2/DAP12 cells[1]. As48 (0.3-30 μM; 0-120 min) activates TREM2 signaling in HMC3 TREM2 OE human microglial cells by inducing dose- and time-dependent SYK phosphorylation[1]. As48 (25 μM; 30 min) enhances phagocytic activity in BV2 murine microglial cells by twofold compared to vehicle control, as measured by fluorescent latex bead uptake assay[1]. As48 (1-30 μM; 18 h) inhibits TREM2 ectodomain shedding in HEK293-TREM2 OE cells in vitro in a dose-dependent manner[1]. As48 (10-300 μM; 30 min) does not inhibit the proteolytic activity of recombinant human ADAM10 or ADAM17 at concentrations up to 300 μM, as measured by fluorogenic protease activity assay[1].
References:
[1]. Cho S, et al. As48, a first-in-class dual-function TREM2 modulator: Receptor activation and shedding inhibition. Biomed Pharmacother. 2025;193:118862.
In Vitro, As48 (0.1-1000 μM; 10 min) binds directly to recombinant human TREM2 protein with a K0 of 12.48 μM, as measured by TRIC binding assay[1]. As48 (0.01-100 μM; 10 min) binds to recombinant human TREM2 with a KD of 13.8 μM, and binds 7-fold more weakly to recombinant human TREM1 (KD = 97.92 μM), as measured by MST binding assay[1]. As48 (30 μM; 20 min) increases the thermal stability of recombinant human TREM2 protein by +3.86°C, as measured by thermal shift assay[1]. As48 (1.23-100 μM) binds directly to biotinylated recombinant human TREM2 protein with a KD of 29.5 μM, as measured by SPR binding assay[1]. As48 (0-300 μM; overnight) exhibits minimal cytotoxicity in HMC3 human microglial cells, with no significant viability loss at concentrations up to 100 μM, as measured by MTS assay[1]. As48 (5-100 μM; 5-60 min) activates TREM2 signaling in HEK293-hTREM2/DAP12 cells by inducing dose- and time-dependent SYK phosphorylation[1]. As48 (0.3-30 μM; 10 min) induces TREM2-dependent intracellular calcium mobilization in HEK293-hTREM2/DAP12 cells[1]. As48 (0.3-30 μM; 0-120 min) activates TREM2 signaling in HMC3 TREM2 OE human microglial cells by inducing dose- and time-dependent SYK phosphorylation[1]. As48 (25 μM; 30 min) enhances phagocytic activity in BV2 murine microglial cells by twofold compared to vehicle control, as measured by fluorescent latex bead uptake assay[1]. As48 (1-30 μM; 18 h) inhibits TREM2 ectodomain shedding in HEK293-TREM2 OE cells in vitro in a dose-dependent manner[1]. As48 (10-300 μM; 30 min) does not inhibit the proteolytic activity of recombinant human ADAM10 or ADAM17 at concentrations up to 300 μM, as measured by fluorogenic protease activity assay[1].
References:
[1]. Cho S, et al. As48, a first-in-class dual-function TREM2 modulator: Receptor activation and shedding inhibition. Biomed Pharmacother. 2025;193:118862.