New insights to advance drug discovery in pain, cancer and inflammation

Published: 27-Apr-2017

Heptares collaboration with AstraZeneca yields novel mechanisms of action highlighted from resolved structures of PAR2 bound to antagonist molecules

Heptares Therapeutics, subsidiary of Sosei, 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.

PAR2 is a G protein-coupled receptor (GPCR) that is a well-validated target for multiple indications in pain, cancer and inflammatory diseases. However, it 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 findings

The companies identified several novel PAR2 antagonists that were then crystallised in complex with the PAR2 receptor. Their X-ray structures were elucidated with high resolution.

This has shed light on 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.

The small molecule antagonist AZ8838, identified 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.

In practice

Fiona Marshall, Chief Scientific Officer of Heptares and Sosei, said: “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.”

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