Definition

An orally bioavailable, dual antagonist of the human prostaglandin E2 receptor subtypes 2 (EP2) and 4 (EP4), with potential immunomodulating and antineoplastic activities. Upon oral administration, the EP2/EP4 antagonist TPST-1495 selectively targets and binds to EP2 and EP4, inhibiting the binding of the immunosuppressive prostaglandin E2 (PGE2) to EP2 and EP4. This prevents the activation of EP2 and EP4, and inhibits PGE2-EP2/EP4-mediated signaling. This inhibits PGE2-driven immune suppression by preventing the PGE2-mediated inhibition of anti-tumor immune effector cells in the tumor microenvironment (TME), such as natural killer (NK) cells, T-lymphocytes, dendritic cells (DCs) and M1 macrophages, and blocking the PGE2-mediated increase in suppressive immune cells, such as myeloid derived suppressor cells (MDSCs), M2 macrophages, and regulatory T cells (Tregs). This inhibits the proliferation of tumor cells in which the PGE2-EP2/4 signaling pathway is over-activated. EP2 and EP4, G protein-coupled receptors (GPCRs) that are overexpressed in certain types of cancers, promote tumor cell proliferation, invasion, survival, and metastasis.