DT-9045

DT-9045 is a first-in-class, orally available small molecule negative allosteric modulator (NAM) of protease-activated receptor 2 (PAR2), developed for immuno-oncology applications. It is designed to overcome resistance to EGFR-targeting therapies and immunotherapies in cancer models by modulating the immune response and addressing tumor-induced immunosuppression. DT-9045 exhibits G-protein biased NAM activity on PAR2, with no impact on the β-arrestin pathway or ligand-induced receptor internalization. Its pharmacological profile includes insurmountable antagonism—preserving efficacy even at high concentrations of activating proteases typical in the tumor microenvironment—and maintained activity at acidic pH, which is characteristic of inflamed or tumoral tissues. Preclinical studies have demonstrated that DT-9045 can potentiate anti-tumor effects when combined with anti-PD1 therapy, suggesting potential to expand responsiveness among patients who do not benefit from current immunotherapies. IND-enabling studies are ongoing, with Phase 1 trials in recurrent or metastatic solid tumors expected to begin by mid-2025[1][2][3][4][6].