TP-18 is a potent, selective, orally available dual PGE2 receptor EP2/EP4 antagonist with IC50 of 9.5/3.3 nM respectively.
TP-18 potently suppressed PGE2-induced β-arrestin recruitment in CHO-EP2 cells and CHO-EP4 cells with IC50 values of 11.1 and 10.5 nM, respectively.
TP-18 displays robust antagonism against EP2 and EP4 in GPCR assay based on Gα16-mediated calcium flux, with high selectivity of >1,000-fold against the EP1 and EP3 receptors.
TP-18 physically occupies the PGE2-binding pockets of EP2 and EP4 structures.
TP-18 triggers CD8+ T cell-mediated anti-tumor immune response to promote tumor regression, demonstrates superior anti-tumor efficacy compared to EP2i, EP4i, and celecoxib.
TP-18 boosts CD8+ T cell response via depleting immunosuppressive VSIG4high tumor-associated macrophages (TAMs).
TP-18 impairs expression of immune checkpoint molecule VSIG4 in TAMs through inactivating Gαs-PKA-CREB signaling.
TP-18 overcomes primary and acquired resistance to anti-PD-1 therapy in colorectal cancer models, improves the efficacy of anti-PD-1 therapy in patient-derived tumor immune organoids.