New structural insight into the highly challenging drug target PAR2 helps paves the way for future therapies in inflammatory pain

Defining the world’s first crystal structures of PAR2 uncovers novel binding sites through advanced drug discovery technologies

Discovery scientists from IMED Biotech Unit in partnership with Heptares have published in Nature the world’s first crystal structure of protease-activated receptor 2 (PAR2) and uncovered novel binding sites.

PAR2 plays a key role in inflammation, and is considered a highly desirable drug target for treatment of oesteoarthric pain. Until now, the discovery of small molecule antagonists to PAR2 has proven very challenging.

Through a long-standing collaboration between AstraZeneca and Heptares accessing its StaR® platform it is the first time the crystal structure of this receptor has been resolved. In one structure the binding site was found to be bound in a fully occluded pocket near the extracellular surface. The buried nature resulted in long residence time of the molecule.  A second structure was solved in complex with an antagonist identified from DNA-encoded library screening in collaboration with XChem. This compound was bound in a remote site outside the helical bundle. A third structure was in complex with a Fab fragment of a blocking antibody.

“Together these structures demonstrate multiple sites of action through different drug modalities, and we now have been able to create lead chemical series against PAR2 to block normal signalling function.” says Niek Dekker, Principal Discovery Scientist, Innovative Medicines and Early Development at AstraZeneca. “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.”

“Heptares StaR technology has been essential to solve the X-ray structures of this unusual GPCR in complex with the novel ligands identified by Astra Zeneca. Structure based design methods can now be used to target the binding sites identified in the X-ray structures which will greatly facilitate efforts to find optimal drug candidates to progress to the clinic for the treatment of inflammatory pain.” says Fiona Marshall, Chief Scientific Officer, Heptares Therapeutics

“We are excited to learn that the antagonist discovered using our DEXTM platform binds at a previously unknown binding site,” said Matt Clark, Senior Vice President for Research at X-Chem.  “We believe this observation further illustrates the power of unbiased DEXTM selection in identifying new binding sites and modes of binding, even against difficult targets like PAR2.”

Demonstrating the presence of multiple allosteric sites within PAR2 offers alternative approaches for structure based drug design. The compound series are progressing through drug discovery at AstraZeneca on this previously intractable, yet highly desirable drug target.

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 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 X-Chem

X-Chem, Inc. is a privately-owned biotechnology company based in Waltham, Mass. The company’s mission is to apply its powerful product engine to the discovery of small molecule compounds against high-value therapeutic targets. X-Chem has established partnerships with Roche, AstraZeneca, Bayer, Pfizer, Alexion, MD Anderson Cancer Center, Sanofi, Janssen, and several other leading pharmaceutical companies, biotechnology organizations, and academic centers. For further information on X-Chem, please visit: http://www.x-chemrx.com/.