Targeting EP2 Receptor for Drug Discovery: Strengths, Weaknesses, Opportunities, and Threats (SWOT) Analysis

Abstract

Cyclooxygenase-1 and -2 (COX1 and COX2) derived endogenous ligand prostaglandin-E₂ (PGE₂) triggers several physiological and pathological conditions. It mediates signaling through four G-protein coupled receptors, EP1, EP2, EP3, and EP4. Among these, EP2 is expressed throughout the body including the brain and uterus. The functional role of EP2 has been extensively studied using EP2 gene knockout mice, cellular models, and selective small molecule agonists and antagonists for this receptor. The efficacy data from in vitro and in vivo animal models indicate that EP2 receptor is a major proinflammatory mediator with deleterious functions in a variety of diseases suggesting a path forward for EP2 inhibitors as the next generation of selective anti-inflammatory and antiproliferative agents. Interestingly in certain diseases, EP2 action is beneficial; therefore, EP2 agonists seem to be clinically useful. Here, we highlight the strengths, weaknesses, opportunities, and potential threats (SWOT analysis) for targeting EP2 receptor for therapeutic development for a variety of unmet clinical needs.

Figure 1

(A) Illustration of EP2 involvement in gliosis and subsequent neurodegenerative pathologies such as epilepsy, memory and cognitive deficits, and Alzheimer’s disease type dementia. (B) EP2 involvement in inflammation driven cancer proliferation, metastasis, and tumor development. EP2 inhibition with a small molecule antagonist should be therapeutically beneficial.

Figure 2

EP2 antagonists so far tested in animal proof-of-concept studies. Among these, AH 6809 is a dual antagonist of EP1 and EP2 receptors with equal potency.

Figure 3

EP2 and EP4 agonists used in the described studies.