Discovery of 2<i>H</i>-Indazole-3-carboxamide Derivatives as Novel Potent Prostanoid EP4 Receptor Antagonists for Colorectal Cancer Immunotherapy
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 Lü
Abstract
Nowadays, small-molecule drugs have become an indispensable part of tumor immunotherapy. Accumulating evidence has indicated that specifically blocking PGE 2 /EP4 signaling to induce robust antitumor immune response represents an attractive immunotherapy strategy. Herein, a 2 H -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.