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

Prostaglandin E2 (PGE(2)) receptor 4 (EP4) isone of fourEP receptors commonly upregulated in the tumor microenvironment andplays vital roles in stimulating cell proliferation, invasion, andmetastasis. Biochemical blockade of the PGE(2)-EP4signaling pathway is a promising strategy for controlling inflammatoryand immune related disorders. Recently combination therapies of EP4antagonists with anti-PD-1 or chemotherapy agents have emerged inclinical studies for lung, breast, colon, and pancreatic cancers.Herein, a novel series of indole-2-carboxamide derivatives were identifiedas selective EP4 antagonists, and SAR studies led to the discoveryof the potent compound 36. Due to favorable pharmacokineticsproperties and good oral bioavailability (F = 76%),compound 36 was chosen for in vivo efficacystudies. Compound 36 inhibited tumor growth in a CT-26colon cancer xenograft better than E7046 and a combination of 36 with capecitabine significantly suppressed tumor growth(TGI up to 94.26%) in mouse models.