Female Scientific Research Team With Clear Solution In LaboratorHeptares Therapeutics, the wholly owned subsidiary of Sosei Group Corporation, describes new insights for drug discovery from the first resolved high-resolution X-ray crystal structures of the Protease-Activated Receptor-2 (PAR2) in complex with antagonist molecules.

The research, which reports on findings from PAR2 bound and inactivated by small molecule and antibody antagonists, was published online in Nature and can be accessed at http://dx.doi.org/10.1038/nature22309.

PAR2 is a G protein-coupled receptor (GPCR) that is a well-validated target for multiple indications in pain, cancer and inflammatory diseases, but which has previously proved to be intractable to conventional drug discovery approaches.

PAR2 is an unusual GPCR that is activated by cleavage with a protease enzyme such that the cleaved part of the receptor acts as its own ligand. Because of this unusual mechanism of activation, it has been extremely difficult to identify PAR2 antagonists for development as new medicines.

The Nature publication resulted from a long-term collaboration between scientists at Heptares and AstraZeneca, who have applied their respective technologies (including Heptares’ proprietary StaR platform) and complementary discovery capabilities to identify several novel PAR2 antagonists. These antagonists were then crystallised in a complex with the PAR2 receptor and their X-ray structures were elucidated with high resolution.

The structures have provided Heptares and AstraZeneca with a unique understanding of the precise mechanisms of action of these antagonists, which bind at novel allosteric sites distant from the ligand-binding site. In turn, these structural insights are providing a basis for further development of the small molecule drug candidates for a range of therapeutic indications.

Specifically, the authors describe how the small molecule antagonist AZ8838, identified by AstraZeneca by high-throughput screening, binds to PAR2 in a fully occluded and previously inaccessible pocket near the extracellular surface of the receptor.

A second molecule, AZ3451, identified by screening compounds with the PAR2-StaR protein, was found to bind a remote allosteric site that is thought to prevent structural rearrangements required for receptor activation and signalling.

The scientists also discovered that a blocking antibody fragment binds to the extracellular surface of the receptor to prevent access of the ligand to the binding site.

Fiona Marshall, Chief Scientific Officer of Heptares and Sosei, said:  “The research being undertaken by Heptares and AstraZeneca around PAR2 is truly cutting-edge and demonstrates the synergies in our respective capabilities and the clear benefits that structural insights can bring to drug discovery.”

“PAR2 is an important drug target that has so far eluded attempts to create effective drugs that block its activity. The work we are doing with AstraZeneca will hopefully redress this situation to provide new medicines across pain and other indications.”

Niek Dekker, Principal Discovery Scientist, Innovative Medicines and Early Development at AstraZeneca, added: “Access to the Heptares StaR technology enabled us to progress available small molecule actives on PAR2 to credible lead series, where we earlier struggled to develop our chemistry. We are particularly excited by the functional and binding study data from one of the lead series as this exhibits slow binding kinetics, which is an attractive feature for this target.”