EP₄ Antagonist 14

EP₄ antagonist 14 is an antagonist of the prostaglandin E₂ (PGE₂) receptor subtype EP₄ with an IC₅₀ value of 1.1 nM in a reporter assay using HEK293 cells expressing the human receptor.¹ It inhibits PGE₂-induced β-arrestin recruitment in the same cells (IC₅₀ = 0.9 nM). EP₄ antagonist 14 (10 µM) decreases PGE₂-induced expression of mRNA encoding Il-4, macrophage mannose receptor 1 (Mrc1), chitinase-like protein 3 (Chil3), chemokine (C-X-C) motif ligand 1 (Cxcl1), triggering receptor expressed on myeloid cells 2 (Trem2), and arginase-1 (Arg1), in RAW 264.7 macrophages. In vivo, EP₄ antagonist 14 (30 mg/kg per day), in combination with an anti-PD-1 antibody, inhibits tumor growth and increases infiltration of CD8⁺ T cells into tumors in a CT26 murine colon cancer model.

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1. Cheng, Z., Wang, Y., Zhang, Y., et al. Discovery of 2H-indazole-3-carboxamide derivatives as novel potent prostanoid EP₄ receptor antagonists for colorectal cancer immunotherapy. J. Med. Chem. 66(9), 6218-6238 (2023).