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Heptares Solves First Family B GPCR Structure

Published: Tuesday, September 11, 2012
Last Updated: Tuesday, September 11, 2012
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Heptares Therapeutics has used its StaR® technology to solve entirely in-house the first structure of a Family B sub-class G protein-coupled receptor.

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 G protein-coupled receptor (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.


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