Heptares Collaboration With AstraZeneca PLC Yields New Insights To Advance Drug Discovery In Pain, Cancer And Inflammation

LONDON, April 27, 2017 /PRNewswire/ --

Novel mechanisms of action highlighted from resolved structures of PAR2 bound to antagonist molecules - research published in Nature 

Heptares Therapeutics ("Heptares"), the wholly-owned subsidiary of Sosei Group Corporation (TSE Mothers Index: 4565), 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 today 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 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."

About Heptares Therapeutics 

Heptares is a clinical-stage company creating transformative medicines targeting G protein-coupled receptors (GPCRs), a superfamily of 375 receptors linked to a wide range of human diseases. Heptares' proprietary StaR® technology and structure-based drug design (SBDD) capabilities enable us to engineer and develop drugs for highly validated, yet historically undruggable or challenging GPCRs. Using this approach, we are building an exciting pipeline of new medicines (small molecules and biologics) with the potential to transform the treatment of Alzheimer's disease, schizophrenia, cancer immune-oncology, migraine, addiction, metabolic disease and other indications. We have partnerships for our novel candidates and technologies with leading pharmaceutical and biotechnology companies, including Allergan, AstraZeneca, Daiichi Sankyo, Kymab, MedImmune, MorphoSys, Pfizer and Teva.

Heptares is a wholly owned subsidiary of Sosei Group Corporation. For more information, please visit www.heptares.com and www.sosei.com.

HEPTARES is a registered trademark in the EU, Switzerland, US and Japan;

StaR® is a registered trademark in the EU and Japan.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com.

About Sosei 

Sosei is a biopharmaceutical company originating from Japan but with global presence. Sosei's primary business model is based on identifying novel and/or differentiated product assets or technology platforms and, through supporting these in preclinical and clinical development and establishing commercial partnerships, advancing new medicines to patients worldwide. For more information about Sosei, please visit www.sosei.com.

Contact Information

Citigate Dewe Rogerson (for Heptares)
Mark Swallow, David Dible
Heptares Therapeutics Ltd
Malcolm Weir, Chief Executive Officer

*Using X-Chem's DEX™ screening technology  


Cheng, RK et al. Structural insight into allosteric modulation of protease-activated receptor 2, (2017) Nature http://dx.doi.org/10.1038/nature22309

SOURCE Heptares Therapeutics

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