Discovery and Characterization of 1<i>H</i>‑1,2,3-Triazole Derivatives as Novel Prostanoid EP4 Receptor Antagonists for Cancer Immunotherapy

The prostanoid EP4 receptor is one of the key receptors associated with inflammatory mediator PGE2-elicited immunosuppression in the tumor microenvironment. Blockade of EP4 signaling to enhance immunity-mediated tumor elimination has recently emerged as a promising strategy for cancer immunotherapy. In our efforts to discover novel subtype-selective EP4 antagonists, we designed and synthesized a class of 1H-1,2,3-triazole-based ligands that display low nanomolar antagonism activity toward the human EP4 receptor and excellent subtype selectivity. The most promising compound 59 exhibits single-digit nanomolar potency in the EP4 calcium flux and cAMP-response element reporter assays and effectively suppresses the expression of multiple immunosuppression-related genes in macrophage cells. On the basis of its favorable ADMET properties, compound 59 was chosen for further in vivo biological evaluation. Oral administration of compound 59 significantly inhibited tumor growth in the mouse CT26 colon carcinoma model accompanied by enhanced infiltration of cytotoxic T lymphocytes in the tumor tissue.前列腺素EP4受体（prostanoid EP4 receptor）是肿瘤微环境中与炎症介质前列腺素E2（PGE2）介导的免疫抑制相关的关键受体之一。靶向阻断EP4信号通路以增强免疫介导的肿瘤清除，近来已成为癌症免疫治疗的极具前景的策略。在本研究中，为发现新型亚型选择性EP4拮抗剂，我们设计并合成了一类基于1H-1,2,3-三唑的配体，该类配体对人源EP4受体展现出低纳摩尔级的拮抗活性，且具备优异的亚型选择性。最具潜力的化合物59在EP4受体钙流检测及环磷酸腺苷（cAMP）应答元件报告基因实验中，均表现出个位数纳摩尔级的活性效价，并可有效抑制巨噬细胞中多种免疫抑制相关基因的表达。鉴于其良好的ADMET（吸收、分布、代谢、排泄、毒性）特性，化合物59被选为进一步开展体内生物学评价的候选化合物。口服给予化合物59，可显著抑制小鼠CT26结肠癌模型的肿瘤生长，同时伴随肿瘤组织内细胞毒性T淋巴细胞浸润程度的显著增强。