Discovery of Novel, Selective Prostaglandin EP4 Receptor Antagonists with Efficacy in Cancer Models.

ABSTRACT

Prostaglandin E2 (PGE2) receptor 4 (EP4) is one of four EP receptors commonly upregulated in the tumor microenvironment and plays vital roles in stimulating cell proliferation, invasion, and metastasis. Biochemical blockade of the PGE2-EP4 signaling pathway is a promising strategy for controlling inflammatory and immune related disorders. Recently combination therapies of EP4 antagonists with anti-PD-1 or chemotherapy agents have emerged in clinical studies for lung, breast, colon, and pancreatic cancers. Herein, a novel series of indole-2-carboxamide derivatives were identified as selective EP4 antagonists, and SAR studies led to the discovery of the potent compound 36. Due to favorable pharmacokinetics properties and good oral bioavailability (F = 76%), compound 36 was chosen for in vivo efficacy studies. Compound 36 inhibited tumor growth in a CT-26 colon cancer xenograft better than E7046 and a combination of 36 with capecitabine significantly suppressed tumor growth (TGI up to 94.26%) in mouse models.