Biased Agonism of GPR84 as a Novel Dual Anti-inflammatory and Pro-repair Mechanism

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.