Selective GPR84 Antagonist

GPR84 is classified as an orphan receptor since its definitive endogenous ligand is undefined. However, it can be activated by medium-chain fatty acids (MCFA) such as decanoic acid, 6-OAU, and diindolylmethane (DIM), indicating the presence of three unique binding sites, which likely correspond to different endogenous ligands. Additionally, the activation of each binding site may lead to different downstream effects, a phenomenon known as signaling bias, which is well-documented within the GPCR superfamily.

GPR84 is a pro-inflammatory target primarily expressed on cells associated with the immune system and its expression levels increase significantly during periods of inflammatory stress. Inhibition of GPR84 can inhibit neutrophil and macrophage migration and reduce cytokine release.

GPR84 expression is not restricted to cells in the immune system; it is also expressed in tissues such as the lung, brain, heart, muscle, colon, kidney, liver, intestine and adipose. Through its role in inflammation, GPR84 may be a mediator of the relationship between inflammation, obesity and diabetes. Rodent models suggest that GPR84 expression is up-regulated in adipocytes in response to TNF-α released from infiltrating macrophages, and that this in turn can lead to a down-regulation in adiponectin expression in adipocytes. Adiponectin is known to have anti-diabetic, anti-inflammatory, and anti-atherogenic effects, and it also functions as an insulin sensitizer.

We believe that the GPR84 receptor could be an important biological target in several therapeutic areas of interest. GPR84 is broadly expressed and may play an interesting role in the relationship between inflammation, obesity and diabetes. Our preclinical research, combined with published work from other groups, indicates a potential role for antagonism of GPR84 in fibrotic diseases, including Non-Alcoholic Steatohepatitis, or NASH, Inflammatory bowel disease, or IBD, and Idiopathic Pulmonary Fibrosis, or IPF.

In January 2023, we nominated LMNL6511 as the candidate selected for clinical development for this program. Through our internal drug discovery and lead optimization work we have been able to develop LMNL6511, a new structural class of high potency, small molecule antagonist of GPR84. Subject to continued satisfactory results in ongoing clinical trial application (CTA)-enabling work, we expect to seek approval to commence a first-in-human Phase 1 clinical trial of LMNL6511, in healthy volunteers, in the second half of 2023.