LONDON, December 8, 2016 /PRNewswire/ --
Chemokine receptor family plays key role across multiple disease areas and represents an important target for drug discovery and development
Publication in Nature describes novel, intracellular allosteric binding site in CCR9 receptor
Heptares Therapeutics ("Heptares"), the wholly-owned subsidiary of Sosei Group Corporation (TSE Mothers Index: 4565), announces that its scientists have solved the high-resolution X-ray crystal structure of the CCR9 receptor, a member of the chemokine receptor family (Oswald et al, Nature). This family of G protein-coupled receptors (GPCRs) has diverse roles in immune defence by controlling the migration, activation and survival of immune cells, hence chemokine receptors are important drug targets in a wide range of diseases. The CCR9 receptor itself is central to leukocyte (white blood cell) recruitment to the gut and represents a therapeutic target in inflammatory bowel diseases, an area of increasing interest for Heptares.
Fiona Marshall, Chief Scientific Officer at Heptares and at Sosei, commented: "The availability of a high-resolution structure of the CCR9 receptor in this conformation provides a unique opportunity to apply structure-based drug design to the discovery and optimisation of selective small molecule allosteric modulator drugs not only targeting CCR9 but potentially also other members of the chemokine receptor family. This new structural information adds to the wealth of information the Company has generated using its StaR® platform on GPCRs, and is enabling the Company to apply its structure-based design platform to develop a sustainable pipeline of novel drug candidates in diverse disease areas."
The publication in Nature describes how Heptares scientists solved the X-ray structure of the CCR9 receptor bound to the selective antagonist vercirnon. The research revealed that, surprisingly, vercirnon binds to the intracellular side of the receptor and not to the normal binding site for GPCR ligands. In binding to this allosteric site on CCR9, vercirnon exerts its antagonistic effect by preventing CCR9 from interacting with signaling molecules inside the cell. This breakthrough finding has opened a new avenue for investigation across the chemokine receptor family. Heptares scientists have previously identified allosteric binding sites on other GPCRs including the glucagon receptor (Jazayeri et al, reference below).
Only two drugs that target chemokine receptors from over 50 entering clinical development have reached the market: maraviroc for HIV targeting CCR5, and plerixafor for stem-cell mobilization targeting CXCR4. The low success rate is thought to be in part due to limited understanding of the mechanisms of action of chemokine receptors, and an inability to optimise candidate compounds in the absence of structural information. Heptares believes that the new information has the potential to improve the success rate of efforts to develop small molecule therapeutics against chemokine receptors.
Oswald, C. et al (2016) Nature - click here
Jazayeri, A. et al (2016) Nature - click here
Notes to Editors
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, Kymab, MedImmune, MorphoSys, Pfizer and Teva.
HEPTARES is a registered trademark in the EU, Switzerland, US and Japan;
StaR® is a registered trademark in the EU and Japan.
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 http://www.sosei.com.
SOURCE Heptares Therapeutics