Discovery of ACT‐1002‐4271 as a Dual Prostaglandin E2 Receptor 2/Prostaglandin E2 Receptor 4 Antagonist with In Vivo Anti‐Tumor Efficacy

Prostaglandin E2 (PGE2) signaling via receptors prostaglandin E2 receptor 2 (EP2) and prostaglandin E2 receptor 4 (EP4) is involved in various aspects of cancer and has been shown to promote tumor progression, metastasis, and immune evasion. Inhibition of PGE2 signaling by blockade of the EP2 and EP4 receptors has the potential to counteract the tumor-promoting effects of PGE2. Herein, the discovery of compound 30 (ACT-1002-4271), a dual EP2/EP4 antagonist with single-digit nanomolar potency on both receptors, is presented. The medicinal chemistry strategy is based on fine-tuning of the substitution pattern on an EP2 selective starting point to achieve dual EP2/EP4 antagonism. ACT-1002-4271 demonstrated significant antitumor efficacy in an experimental mammary tumour-6 mouse model when administered subcutaneously.