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

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Prostaglandin E2 (PGE2) receptor 4 (EP4) is upregulated in the tumor microenvironment, promoting cancer cell proliferation, invasion, and metastasis.
• Targeting the PGE2-EP4 signaling pathway is a promising strategy for cancer therapy and immune-related disorders.
• Combination therapies involving EP4 antagonists are emerging in clinical studies for various cancers.

Purpose of the Study:

• To identify novel selective EP4 antagonists.
• To evaluate the in vivo efficacy of a lead compound in preclinical cancer models.

Main Methods:

• Synthesis and structure-activity relationship (SAR) studies of indole-2-carboxamide derivatives.
• Pharmacokinetic profiling and oral bioavailability assessment.
• In vivo efficacy studies using CT-26 colon cancer xenografts in mouse models.

Main Results:

• Discovery of a potent and selective EP4 antagonist, compound 36, from a novel series of indole-2-carboxamide derivatives.
• Compound 36 exhibited favorable pharmacokinetics and 76% oral bioavailability.
• Compound 36 inhibited tumor growth in CT-26 colon cancer xenografts and significantly suppressed tumor growth when combined with capecitabine (TGI up to 94.26%).

Conclusions:

• Compound 36 is a potent EP4 antagonist with promising preclinical efficacy.
• The combination of compound 36 with capecitabine shows significant potential for colon cancer treatment.