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

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.

Call for proposal

H2020-MSCA-IF-2020
See other projects for this call

Coordinator

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Address
Wellington Square University Offices
OX1 2JD Oxford
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 224 933,76