Design of Dual EP2/EP4 Antagonists through Scaffold Merging of Selective Inhibitors

Prostaglandin E2 (PGE2) plays a key role in various stages of cancer. PGE2 signals through the EP2 and the EP4 receptors, promoting tumorigenesis, metastasis, and/or immune suppression. Dual inhibition of both the EP2 and the EP4 receptors has the potential to counteract the effect of PGE2 and to result in antitumor efficacy. We herein disclose for the first time the structure of dual EP2/EP4 antagonists. By merging the scaffolds of EP2 selective and EP4 selective inhibitors, we generated a new chemical series of compounds blocking both receptors with comparable potency. In vitro and in vivo profiling suggests that the newly identified compounds are promising lead structures for further development into dual EP2/EP4 antagonists for use in cancer therapy. PGE2 promotes cancer progression by activation of the EP2 and EP4 prostaglandin receptors. We are reporting the development of dual EP2/EP4 antagonists. Our strategy relies on merging the scaffolds of EP2 selective (I) and EP4 selective (II) antagonists. A series of lead compounds was identified and shown to have promising drug-like properties.image