Heptares technology enables breakthrough in drug discovery collaboration with Astrazeneca

Stable receptor, x-ray structure and hit series generated for PAR2, a previously intractable target for pain and inflammation

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LONDON and BOSTON—Heptares Therapeutics, the clinical-stage GPCR structure-guided drug discovery and development company, has announced significant progress in its drug discovery collaboration with AstraZeneca.
Using Heptares proprietary StaR® technology, the first-ever stable version of Protease-Activated Receptor-2 (PAR2) in a therapeutically relevant form has been generated, from which its X-ray structure has been solved. PAR2 is a G protein-coupled receptor (GPCR) that is a well-validated target for multiple indications in pain and inflammatory diseases.
Working with scientists at AstraZeneca, the PAR2 StaR protein was used to screen compound libraries resulting in the identification of a hit series of small molecules that bind and block its activity. The x-ray structure information, which yields new details about the unusual binding pocket of PAR2, is now being used at AstraZeneca to further optimize the hit molecules; to increase their binding affinity, potency as antagonists as well as improving their drug-like properties (e.g., oral bioavailability and stability).
PAR2 is an unusual GPCR that is activated by cleavage with a protease enzyme. The receptor is expressed on primary afferent neurons involved in pain sensation. PAR2 appears to play a key role in neurogenic inflammation and pain in particular associated with cancer, osteoarthritis and gastrointestinal pain. Because of the unusual mechanism of activation, which leaves part of the receptor to act as its own ligand, it has proved extremely difficult to identify small molecule antagonists which could be used as a treatment for such pain conditions.
Malcolm Weir, Heptares CEO, said: “The partnership with AstraZeneca is an exciting example of how the use of our respective technologies, complementary discovery capabilities and excellent working relationships can lead to significant advances in drug discovery for targets that have previously proved intractable to the discovery of small molecule drugs. We look forward to continued success from this collaboration.”
Heptares is a clinical-stage company creating transformative medicines targeting G protein-coupled receptors (GPCRs), a superfamily of receptors linked to a wide range of human diseases. The company’s proprietary structure-based drug design technology enables it to engineer drugs for highly validated, yet historically undruggable or challenging, GPCRs. Using this approach, Heptares has built a pipeline of new medicines with the potential to transform the treatment of Alzheimer’s disease, ADHD, diabetes, schizophrenia, migraine and other diseases. Company partners include Cubist, MorphoSys, Takeda, AstraZeneca and MedImmune.
At the heart of Heptares’ integrated structure-based design platform for GPCR-focused drug discovery and development is its proprietary StaR technology. A StaR protein is a stabilized GPCR with a small number of point mutations that greatly improve its thermostability without disrupting its pharmacology. StaR technology allows the generation of stable, functionally relevant, purified GPCRs in their natural pharmacological conformations (agonist or antagonist), including orphan receptors, that retain their expected drug-binding characteristics. Whereas unstable wild-type proteins are intractable to structural studies, StaR proteins allow structure determination and provide the launch pad for an SBDD (Skeletal Biology Development & Disease) approach to GPCR drug targets that for the first time enables determination of 3D structures of GPCRs and complexes with bound ligands by X-ray crystallography and Biophysical Mapping™; deployment of compound screening and advanced fragment-based drug discovery approaches to GPCRs; full integration of GPCR pharmacology and medicinal chemistry; and discovery of novel agents directed towards high-value yet historically challenging or undruggable GPCR drug targets.
Heptares’ StaR platform also offers a breakthrough solution to the main challenge associated with making antibodies against GPCRs: producing purified, properly folded and functional protein when removed from the cell membrane for use as an antigen. Furthermore, StaR proteins preserve biologically relevant epitopes, thereby enabling generation of diverse panels of functional antibodies.
On January 23, Heptares announced that the Malcolm Campbell Memorial Prize for 2015 has been awarded to Miles Congreve (vice president of chemistry), Fiona Marshall (chief scientific officer and co-founder) and Malcolm Weir (CEO and co-founder) for the seminal contributions to GPCR drug discovery made by Heptares Therapeutics since the company was founded in 2007.
GPCRs form the most important family of drug targets in the pharmaceutical industry and are linked to a wide range of disease areas; they are the targets for approximately 40 percent of all existing drugs.
The Prize, awarded by the UK Royal Society of Chemistry’s Biological and Medicinal Chemistry Sector, is in recognition of work that has included building the world-renowned StaR® technology platform, which enables precision drug design based on structural information for validated and challenging GPCRs, and the invention of a number of clinical candidates with potential to transform the treatment of a wide range of human diseases. Such candidates include the world’s first selective M1 agonist, which is in clinical studies for improving learning and memory in patients with Alzheimer’s disease, schizophrenia and other related diseases. Heptares is also advancing a non-stimulant medicine targeting the adenosine A2A receptor for treating attention deficit hyperactivity disorder (ADHD).

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