2. Academic Validation
  3. Discovery of 2 H-Indazole-3-carboxamide Derivatives as Novel Potent Prostanoid EP4 Receptor Antagonists for Colorectal Cancer Immunotherapy

Discovery of 2 H-Indazole-3-carboxamide Derivatives as Novel Potent Prostanoid EP4 Receptor Antagonists for Colorectal Cancer Immunotherapy

  • J Med Chem. 2023 May 11;66(9):6218-6238. doi: 10.1021/acs.jmedchem.2c02058.
Zhiyuan Cheng 1,  Yijie Wang 1,  Yao Zhang 1,  Chan Zhang 1,  Mengru Wang 2,  Wei Wang 1,  Jiacheng He 1,  Yang Wang 3,  Hankun Zhang 1,  Qiansen Zhang 1,  Chunyong Ding 4,  Deyan Wu 5 6,  Linlin Yang 2,  Mingyao Liu 1,  Weiqiang Lu 1
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
  • 2 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450052, Henan, China.
  • 3 Department of Urology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
  • 4 Targeted Drug Research Center of Digestive Tract Tumor, Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 5 School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 6 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
PMID: 36880691 DOI: 10.1021/acs.jmedchem.2c02058
Abstract

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.

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