Discovery of 2H-Indazole-3-carboxamide Derivatives as Novel Potent Prostanoid EP4 Receptor Antagonists for Colorectal Cancer Immunotherapy.
Discovery of 2H-Indazole-3-carboxamide Derivatives as Novel Potent Prostanoid EP4 Receptor Antagonists for Colorectal Cancer Immunotherapy.
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DOI：
10.1021/acs.jmedchem.2c02058
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发表时间：
2023-03
影响因子：
7.3
通讯作者：
Zhiyuan Cheng;Yijie Wang;Yao Zhang;Chan Zhang;Mengru Wang;Wei Wang;Jiacheng He;Yang Wang;Hankun Zhang;Qiansen Zhang;Chunyong Ding;Deyan Wu;Linlin Yang;Mingyao Liu;Weiqiang Lu
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文献类型：
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作者：
Zhiyuan Cheng;Yijie Wang;Yao Zhang;Chan Zhang;Mengru Wang;Wei Wang;Jiacheng He;Yang Wang;Hankun Zhang;Qiansen Zhang;Chunyong Ding;Deyan Wu;Linlin Yang;Mingyao Liu;Weiqiang Lu
如今，小分子药物已成为肿瘤免疫治疗中不可或缺的一部分。越来越多的证据表明，特异性阻断PGE 2/EP 4信号传导以诱导强大的抗肿瘤免疫应答代表了一种有吸引力的免疫治疗策略。本文中，通过筛选我们的内部小分子文库，将含有2 H-吲唑-3-甲酰胺的化合物1鉴定为EP 4拮抗剂。系统的结构-活性关系探索导致化合物14的发现，其在一组细胞功能测定中显示出单纳摩尔EP 4拮抗活性、高亚型选择性和有利的药物样特征。此外，化合物14显著抑制巨噬细胞中多种免疫抑制相关基因的上调。口服施用化合物14（作为单一疗法或与抗PD-1抗体组合）在同基因结肠癌模型中通过增强细胞毒性CD 8 + T细胞介导的抗肿瘤免疫而显著损害肿瘤生长。因此，这些结果证明了化合物14作为开发用于肿瘤免疫治疗的新型EP 4拮抗剂的候选物的潜力。
Nowadays, small-molecule drugs have become an indispensable part of tumor immunotherapy. Accumulating evidence has indicated that specifically blocking PGE2/EP4 signaling to induce robust antitumor immune response represents an attractive immunotherapy strategy. Herein, a 2H-indazole-3-carboxamide containing compound 1 was identified as a EP4 antagonist hit by screening our in-house small-molecule library. Systematic structure-activity relationship exploration leads to the discovery of compound 14, which displayed single-nanomolar EP4 antagonistic activity in a panel of cell functional assays, high subtype selectivity, and favorable drug-like profiles. Moreover, compound 14 profoundly inhibited the up-regulation of multiple immunosuppression-related genes in macrophages. Oral administration of compound 14, either as monotherapy or in combination with an anti-PD-1 antibody, significantly impaired tumor growth via enhancing cytotoxic CD8+ T cell-mediated antitumor immunity in a syngeneic colon cancer model. Thus, these results demonstrate the potential of compound 14 as a candidate for developing novel EP4 antagonists for tumor immunotherapy.