Evaluation of novel PAR-2 inhibitors in cellular proliferation. Summer Student Placement Project (£1,600). Professor Robin Plevin and Dr Kathryn McIntosh

Protease-activated receptor-2 (PAR-2) is a member of a family of G-protein coupled receptors regulated by a unique mechanism of activation, whereby a serine protease, exemplified by thrombin, is able to cleave the N-terminus of the receptor to reveal a tethered ligand which stimulates the receptor. There are four member of this family (PARs 1-4) each with their own specific enzyme activators and activating peptide sequences. Each receptor has a recognised distribution and range of physiological functions.
PAR-2 is strongly expressed in both epithelial cells and cell of the immune system and a large body of evidence implicates the receptor in the genesis of inflammation. Using PAR-2 deficient mice, our group in collaboration with others, has demonstrated a key role for both rheumatoid and osteoarthritis underpinned by effects upon Th17 responses. Unlike PAR-1 however, there has been relatively little success in the developing specific inhibitors of PAR-2, previous studies including a number from our group has demonstrated low potency and relatively poor selectivity of existing drugs. Recently however, a new orally available and relatively potent PAR-2 antagonist has been identified, known as GB88. Thus, there is the potential to determine experimentally the effect of pharmacological blockade of PAR-2 in a number of different disease conditions including not only inflammation but also cancer. Recent studies implicate PAR-2 in cancers of the breast, prostate and colon.
Recently in our laboratory we have generated a number of novel lead compounds based on the GB88 scaffold. We wish to determine if in addition to GB88, these agents can modulate PAR-2 activation and as a result cellular proliferation. Therefore in this summer project we will;
1) Assess the effectiveness of inhibitor drugs on initial PAR-2 activation
2) Examine the effect of PAR-2 activation on cell cycle progression and determine if PAR-2 antagonists can inhibit PAR-2 mediated proliferation.

Biochemical society summer internship - externally funded £1,600