Preclinical validation of novel PAR-2 inhibitors for the treatment of Osteoarthritis and Cancer

Project: Research

Project Details


Preclinical validation of novel PAR-2 inhibitors for the treatment of Osteoarthritis and Cancer.

Protease-activated Receptor 2 (PAR-2) is a member of a unique family of G-protein coupled receptors activated by serine protease cleavage of the N-terminus to generate a new tethered ligand. The distribution of this receptor, up-regulation by cytokines and activation by proteases, strongly suggests a role in inflammation. Indeed, we have established a key role for PAR-2 in chronic joint disease and the group are world leaders (Crilly et al., 2012; Ferrell et al., 2010; Ferrell et al., 2003; Kelso et al., 2006). Recently, we established for the first time a role for PAR-2 in osteoarthritis a condition affecting more than 4.4 million sufferers in the UK and a cost to society estimated at over £1B annually. Our current studies show that mice lacking the PAR-2 gene are protected from arthritis for up to a year, a breakthrough finding. Given the paucity of drugs for this disease our data highlights the clinical potential of PAR-2 antagonism. PAR-2 inhibition may also be of benefit in other conditions, for example in cancer, where recent studies have linked cancer progression to the inflammatory environment.
To date the translational aspect of PAR-2 biology has developed slowly due to the lack of potent and selective antagonists, although recently a number of moderately potent putative PAR-2 inhibitors have been identified. One of these, GB88, has also good oral availability. In our hands we find that GB88 functions as a partial agonist, making predictions as to its clinical value difficult. Therefore new and better prototype compounds are required to validate PAR-2 as a bonafide target in disease pathology. We have now identified two new lead compounds (141/2 and 143/1) which have a better antagonist profile (see figure 1 for 141/2), lacking the partial agonist activity of GB88. Our project is to determine if these drugs are effective in disease models, providing critical proof of concept data.

pFact ID (Internal Reference): 9932
RKES Reference (Internal Reference): 130814

SULSA (University Administered): £49,073.00, fEC% 49.00%

1/02/14 → 30/09/15

Layman's description

Developing novel inhibitors of the pro-inflammatory receptor PAR2 to treat Osteoarthritis and cancer.
Short titlePAR2 antagonists
Effective start/end date1/02/1430/09/15