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

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.