A variety of cancers over-produce ligands of GPCRs expressed by specific immune cells to shut down their surveillance. It is the case for adenosine via A2a and A2b receptors, but also for prostaglandin E2 ( PGE2 ), produced by COX2 positive tumors, that activates the prostaglandin receptor 4 ( EP4R ). Antagonizing EP4 receptor is therefore a novel therapeutic approach to restore cancer recognition by the immune system and combat its progression.

Program description

EP4 receptor antagonist (DT-9081)

  • Discovery
  • Candidate
  • Preclinical
  • Phase I

Domain has designed a small molecule drug candidate DT-9081. Together with tumor profiling, the company has translated a complete and robust biomarker strategy monitoring target engagement and efficacy to support clinical development and cancer type prioritization.

The candidate entered clinical trials in 2022. DT-9081 is being evaluated in the EPRAD study, an open-label Phase I trial at multiple centers for patients with advanced solid tumors that have recurred or spread. Data will be collected on the drug’s tolerability, pharmacokinetics, pharmacodynamics, and initial efficacy in patients who have failed standard therapies.

For further information please refer to NCT05582850.

Additional resources

DT095895, a selective EP4 receptor antagonist with monotherapy efficacy in syngeneic mouse model(s) and best-in-class properties

This poster presents the complete characterization of Domain drug candidate benchmarked to EP4 antagonist molecules currently in the clinic and demonstrating a best-in-class potential.

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DT-9081, a selective EP4 receptor antagonist which synergizes with immune checkpoint inhibitors to induce complete responses in syngeneic murine cancer models

Phase Ia clinical candidate DT-9081, a selective EP4 receptor antagonist, was designed to counteract the PGE2-immunosuppressive effects in the TME and to synergize with ICI. DT-9081 in vivo efficacy, in combination with ICI in murine syngeneic models, is presented.

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A first-in-human trial of DT-9081 selective EP4 receptor antagonist, in patients with advanced, recurrent or metastatic solid tumors

DT-9081 is a new small molecule, orally administered, highly selective antagonist of EP4R developed to overcome the immune-suppressive effects of PGE2, and to reverse the resistance to immune checkpoint blockers.
DT-9081 has demonstrated significant anti–tumor activity as monotherapy and in combination with immunotherapeutic agents in several syngenic murine cancer models (CT26 colorectal tumor model and MCA205 sarcoma model).

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Other programs

Merck is one of Domain Therapeutics’s partners

A2aR/A2bR antagonist (M1069)


Anti-CCR8 antibody (DT-7012)