2. Academic Validation
  3. Subtle Structural Modifications Spanning from EP4 Antagonism to EP2/EP4 Dual Antagonism: A Novel Class of Thienocyclic-Based Derivatives

Subtle Structural Modifications Spanning from EP4 Antagonism to EP2/EP4 Dual Antagonism: A Novel Class of Thienocyclic-Based Derivatives

  • J Med Chem. 2025 Jan 23;68(2):1587-1607. doi: 10.1021/acs.jmedchem.4c02241.
Zhiyuan Cheng 1,  Yao Zhang 1,  Limin Du 2,  Wei Wang 1,  Xiaolei Chai 1,  Mengxian He 1,  Hankun Zhang 1,  Deyan Wu 3 4,  Jian Lu 1,  Sen Zhang 5,  Bo Feng 5,  Linlin Yang 2,  Mingyao Liu 1,  Weiqiang Lu 1 6
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 2 Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, China.
  • 3 School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 4 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 5 Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200020, China.
  • 6 University Engineering Research Center of Oncolytic & Nanosystem Development, Nanning, Guangxi 530021, China.
PMID: 39757828 DOI: 10.1021/acs.jmedchem.4c02241
Abstract

The development of dual prostaglandin E2 receptors 2/4 (EP2/EP4) antagonists represents an attractive strategy for Cancer Immunotherapy. Herein, a series of 4,7-dihydro-5H-thieno[2,3-c]pyran derivatives with potent EP2/EP4 dual antagonism were discovered by fine-tuned structural modifications. The biphenyl side chain was found to be the key pharmacophore for the transition from EP4 antagonism to EP2/EP4 dual antagonism. The introduction of large sterically hindered segments posed challenges on obtaining EP2 potency, while having minimal impact on EP4 potency. Molecular dynamics simulations verified that the EP2 pocket is relatively narrow compared to EP4, and the key residues surrounding the EP2 pocket impose spatial restrictions on the entry of antagonists. Representative compound 29 (CZY-1068) significantly reduced PGE2-induced expression of immunosuppression-related genes in macrophages. Notably, compound 29 elicited robust antitumor efficacy in the syngeneic MC38 tumor model. Taken together, this study provides a proof-of-concept for obtaining novel potent dual EP2/EP4 antagonists based on rational structural modifications.

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