Dual EP2/EP4 Antagonism

Prostaglandin E2 (PGE2) is produced by both the tumor and stroma and drives tumor growth while acting as a potent immunosuppressive factor in the TME. Prostaglandin signaling promotes the differentiation of and skewing towards immunosuppressive cell populations (e.g., myeloid-derived suppressor cells, regulatory T cells, and M2 macrophages) in concert with the decrease in the differentiation, maturation, activation and proliferation of inflammatory cell populations (e.g. dendritic cells, NK cells, and CD8 positive T-cells).

Four E-prostanoid receptors (EP1, EP2, EP3, and EP4 respectively) are the primary mediators of prostaglandin signaling in the TME. Data generated by Tempest in addition to extensive published literature indicate that selectively blocking signaling through EP2 and EP4 receptors, and not EP1 and EP3, is the most effective strategy to abrogate prostaglandin driven tumor growth and immunosuppression.

PGE2 Pathway graphic

Tempest has developed TPST 1495, a novel, highly selective and potent EP2-EP4 dual antagonist. In preclinical studies, TPST-1495 is significantly more potent than EP4-only antagnosts.

Tumor burden at 8w of treatment graphic

TPST-1495 is progressing through Phase 1/1b monotherapy and combination studies.