Scaffold Hopping Strategy to Identify Prostanoid EP4 Receptor Antagonists for Cancer Immunotherapy

Area of Science:

• Immunology
• Pharmacology
• Medicinal Chemistry

Background:

• Cancer cells evade immune surveillance by suppressing the immune response.
• Prostaglandin E2 (PGE2) is a key mediator of tumor-induced immunosuppression.
• The EP4 receptor, a target of PGE2, promotes tumor progression and resistance to immunotherapy.

Purpose of the Study:

• To design and synthesize novel EP4 receptor antagonists with improved drug-like properties.
• To evaluate the potential of these antagonists as a therapeutic strategy for cancer immunotherapy.

Main Methods:

• Scaffold hopping strategy was employed to design and synthesize 4,7-dihydro-5H-thieno[2,3-c]pyran derivatives.
• Compound 47 was identified as a potent and selective EP4 antagonist.
• In vitro studies assessed immunosuppression-related gene expression in macrophages.
• In vivo studies evaluated the efficacy of compound 47 in a mouse CT26 colon carcinoma model, alone and in combination with anti-PD-1 antibody.

Main Results:

• Compound 47 demonstrated potent EP4 antagonistic activity and excellent subtype selectivity.
• Compound 47 suppressed the expression of immunosuppression-related genes in macrophages.
• Oral administration of compound 47 significantly enhanced antitumor immune response and inhibited tumor growth in vivo.
• Combination therapy with compound 47 and anti-PD-1 antibody showed synergistic antitumor effects.

Conclusions:

• Selective EP4 receptor antagonists, such as compound 47, represent a promising approach for cancer immunotherapy.
• Compound 47 exhibits favorable drug-like properties and potent antitumor activity.
• Further development of EP4 antagonists holds significant potential for improving cancer treatment outcomes.