Heptares Solves First Family B GPCR Structure

WELWYN GARDEN CITY, England and BOSTON, September 10, 2012 /PRNewswire/ --

Update on novel structures and product pipeline to be presented at Biochemical Society and Royal Society of Chemistry meetings

Heptares Therapeutics today announces that it has used its StaR® technology to solve entirely in-house the first structure of a Family B sub-class G protein-coupled receptor (GPCR). Chief Scientific Officer, Fiona Marshall and Chief Executive Officer, Malcolm Weir, will present views of a high resolution X-ray crystal structure of the Corticotropin Releasing Factor (CRF-1) receptor, together with information about additional novel in-house GPCR structures and Heptares pipeline programmes, at upcoming scientific conferences.*

CRF-1, a drug target for depression and anxiety, is a member of the Family B sub-class of nearly 50 GPCRs, which includes many targets such as GLP-1 (diabetes), PTH (bone) and CGRP (migraine) that have proven intractable to small molecule chemistry. Novel and unexpected insights into receptor topology, conformation and compound binding have been revealed, showing major differences compared to the many already known Family A structures, such as beta-adrenergic receptor. Owing to the close relationship among Family B GPCRs, these insights from the CRF structure will allow high-quality structural models to be generated to the entire family and provide new avenues for discovery, which are being leveraged by the Company using its proprietary structure-based drug design platform.

Heptares is also reporting the first structure for the Muscarinic M₁ receptor in the agonist conformation, and the first structure for the Orexin-2 receptor in an antagonist confirmation. The M₁ structure shows conformational and subtype differences in the ligand binding site compared to muscarinic antagonist-bound structures, and is central to Heptares' selective orthosteric agonist programme for the treatment of Alzheimer's disease and other disorders involving cognitive impairment.

The Orexin-2 structure shows substantial topological differences compared to other peptide Family A receptors, and enables selective drug design to both Orexin-2 (chronic insomnia) and Orexin-1 (anti-craving in addiction and compulsive disorders) subtypes, and modelling of receptor activation.

The Heptares platform is nucleated around its unique ability, using its StaR® technology, to stabilise GPCRs in precisely defined, biologically-relevant conformations. These StaRs® can then be used, based on receptor structural information from X-ray crystallography and Biophysical Mapping™, to design and build (atom-by-atom) small molecules with specified drug action and properties, creating an unparalleled medicinal chemistry capability for addressing extremely difficult GPCR targets.

"No Family B GPCR trans-membrane domain structures have been solved until now, highlighting the power of our StaR® technology. This is a fundamental discovery for GPCR drug design, and for our understanding of the mechanism of action and function of these biologically important receptors," said Fiona Marshall, CSO of Heptares Therapeutics.

"These exciting new structural insights are allowing Heptares to deliver potentially ground-breaking new medicines, which is our sole focus. We have a robust platform and pipeline, with our industry-first selective Muscarinic M₁ agonist expected to enter clinical development next year and further programmes for additional CNS and metabolic disorders advancing well," said Malcolm Weir, CEO of Heptares Therapeutics.

*Conference details

G-protein-coupled-receptors: from structural insights to functional mechanisms
12-14 September 2012
Monash University Prato Centre, Italy

4th RSC/SCI Symposium on GPCRs in Medicinal Chemistry
17-19 September 2012
Lilly UK, Erl Wood, Windlesham, Surrey, UK

About Heptares Therapeutics

Heptares discovers and develops new medicines targeting GPCRs (G protein-coupled receptors), a super-family of drug targets linked to a wide range of human diseases.  Our pharmaceutical partners include Shire, AstraZeneca, MedImmune and Takeda, and we have raised $40M from MVM Life Science Partners, Clarus Ventures, Novartis Venture Fund and Takeda Ventures.

Heptares is pioneering the application of structure-based drug design to the GPCR superfamily of targets and is focused on creating molecules that modulate high-value, yet historically undruggable or challenging, GPCRs.  Our platform incorporates proprietary technologies for engineering stabilised GPCRs in their natural pharmacological conformations, identifying previously unknown chemistries for GPCR protein-drug interactions, and deploying advanced fragment-based approaches to GPCR target space for the first time.

Using this approach, we have generated a broad pipeline of drug candidates for the treatment of serious disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia, depression, chronic insomnia, addiction disorders, and diabetes.  For more information about Heptares, please visit http://www.heptares.com.