GPR84 · Biased Agonism of GPR84 as a Novel Dual Anti-inflammatory and Pro-repair Mechanism
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-07-05 → 2023-07-04
- EU contribution
- €224,934
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Biased Agonism of GPR84 as a Novel Dual Anti-inflammatory and Pro-repair Mechanism
Orphan G-protein-coupled receptor 84 (GPR84) is a receptor that has been linked to cancer, inflammatory and fibrotic diseases. In our previous work, we reported DL-175 as a biased agonist at GPR84 which showed differential signalling via Gi/cAMP and β-arrestin, but which is rapidly metabolised. Herein, we describe an optimisation of DL-175 through a systematic structure–activity relationship (SAR) analysis. This revealed that the replacement of the naphthalene group improved metabolic stability and the addition of a 5-hydroxy substituent to the polar pyridine N-oxide head group, our newly discovered compounds, enhanced the potency for cAMP signalling by three orders of magnitude to low picomolar values. Neither compound showed detectable effects on β-arrestin recruitment up to the highest concentration tested (80 μM). Thus, the new GPR84 agonists displayed excellent potency, selectivity, high G-protein signalling bias and an appropriate in vivo PK profile that will allow investigation of GPR84 biased agonist activity in vivo.
Data: CORDIS, © European Union
Project objective
Elevated local and systemic inflammation has been shown to play a central role in multiple diseases. An important cellular mechanism leading to chronic increased inflammation is dysregulation of the innate immune system. A drug that modulates macrophage function, suppressing the pro-inflammatory response while maintaining pro-repair function would represent a major breakthrough in the treatment of multiple degenerative diseases.Our host group very recently identified a biased agonist of an immunometabolic receptor, GPR84, which failed to induce chemotaxis (pro-inflammatory response) while stimulating phagocytosis (pro-repair response) in both murine and human macrophage (ACS Chem. Biol. 2019). This is an important discovery of a small molecule along with a defined molecular target and cellular mechanism which, for the first time, is capable of blocking a pro-inflammatory response while stimulating a pre-repair response in both mouse and human macrophage. These results are extremely exciting and demonstrate the translational potential of our approach, but the small molecule they identified, while a useful in vitro tool which we have shared with the scientific community, cannot be progressed to in vivo proof-of-concept experiments because it is too metabolically unstable. We are therefore applying to the MSCA IF to seek medicinal chemistry support to drive a hit-to-lead project to evolve our small molecule hit into a lead candidate with appropriate properties for progression in vivo to carry out key proof-of-concept experiments in animal models of inflammation. This in vivo efficacy data will be pivotal to underpin a future funding application to support drug discovery and development campaigns.
Original text from CORDIS.
Participants
- THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OxfordCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union