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.

ACS Medicinal Chemistry Letters

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

Author: Xie, Lingzhi ; Li, Yong ; Qiao, Dandan ; Liu, Zhonghe ; Das, Debasis ; Jia, Jianhe ; Cao, Yuxi ; Wang, Jingbing ; Hong, Jian

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.Biochem. 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 clin. 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.

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Indication	Highest Phase	Country/Location	Organization	Date
Colonic Cancer	Preclinical	-	Anrun Pharmaceutical Technology (Suzhou) Co., Ltd.	-

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