Discovery of DT-9081, a Potent and Orally Bioavailable Small Molecule Antagonist of the EP4 Receptor for the Treatment of Solid Cancers

Abstract The EP4 receptor (EP4R) has emerged as a promising target in immuno-oncology due to its role in modulating tumor immunity and inflammation. Here, we describe the discovery and preclinical development of DT-9081, a clinical candidate EP4R-antagonist that has completed a phase I monotherapy trial for the treatment of solid cancers. A scaffold hopping strategy enabled the identification of a novel chemical series with improved activity and pharmacokinetics. Structure–activity relationship (SAR) studies guided the optimization of lead compounds, culminating in the identification of DT-9081, which exhibits potent EP4R antagonism, favorable ADME characteristics, and an excellent preclinical safety profile. Comprehensive in vitro and in vivo pharmacology data further support the utility of DT-9081 in modulating tumor immunity, providing a compelling rationale for its clinical development in the treatment of solid cancers.