Last updated on April 16, 2014 at 21:24 EDT

Heptares Review Article Highlights Promise of Structure-Based Drug Design for G Protein Coupled Receptors (GPCRs)

April 24, 2012

WELWYN GARDEN CITY, England and BOSTON, April 25, 2012 /PRNewswire/ –

Review published in Trends in Pharmacological Sciences

Heptares Therapeutics, the leading GPCR drug discovery company, announces the recent
publication of a major review of the state of the art for GPCR drug discovery and new
insights that, for the first time, can be obtained from structural biology. The review has
been published online in Trends in Pharmacological Sciences, a Cell Press publication
(ref. 1), and will appear in a special issue of the journal in May, which focuses on
structure-based drug design (SBDD).

The authors from Heptares describe how SBDD is becoming the new paradigm for drug
discovery targeting GPCRs due to recent technological developments in GPCR stabilisation
and novel structural biology. Previously, such approaches were only applicable to soluble
enzymes (such as kinases), for which they have now become integrated into the best
practices of medicinal chemists. The success of SBDD in developing superior drugs
targeting these enzymes has had a significant impact on the pipelines of pharmaceutical
companies, leading to the development of multiple marketed drugs and late-stage pipeline

“The promise of SBDD for GPCRs is that rational design can now be used to identify and
optimise ligands that bind challenging or undruggable GPCR targets,” said Fiona Marshall,
Heptares’ Chief Scientific Officer and co-author of the paper. “These small molecules have
the potential to offer better potency, selectivity and drug-like properties than
previously achievable, establishing a strong basis for the development of much improved
medicines for patients.”

In the review, the authors discuss how the recent availability of X-ray structures of
GPCRs in multiple pharmacologically relevant and ligand-bound conformations, and the
subsequent computational analyses of the ligand-binding sites in these conformations,
provide a new way to assess the druggability of GPCRs. Druggability is the property of a
drug target describing the ease with which a satisfactory small molecule drug may be found
which modulates that target in the desired manner. It is a key factor in prioritization of
drug discovery targets.

As an example of this, the authors describe Heptares’ recent work on the SBDD of A2A
antagonists, illustrating how small, potent and selective compounds can be discovered and
optimised using virtual screening and receptor-ligand models and X-ray co-structures. A
deep druggable region of the A2A binding site revealed by crystallography was targeted and
fully exploited to design orally available and efficacious antagonists (ref. 2). A lead
candidate in this series is the subject of a global licensing agreement recently announced
between Heptares and Shire.

To date, Heptares has applied its GPCR-focused SBDD approach to several other
important GPCRs, enabling the assembly of a rich pipeline of novel drug candidates
targeting serious neurological (CNS) and metabolic disorders, including: highly selective
muscarinic M1 agonists (Alzheimer’s disease and cognitive impairment associated with other
CNS disorders); dual orexin 1/2 antagonist (chronic insomnia); selective orexin 1
antagonist (addiction and compulsive disorders); allosteric modulators of mGluR5 (autism,
Parkinson’s disease, depression and anxiety); GLP-1 agonist (Type 2 diabetes); and CXCR-4
antagonists (cancer/HIV).

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. We
have established R&D collaborations with Shire, Takeda, AstraZeneca, MedImmune and
Novartis Option Fund, and have raised $40M in venture financing from MVM Life Science
Partners, Clarus Ventures, Novartis Venture Fund and Takeda Ventures. Heptares is an
industry pioneer in GPCR structure-based drug design and has built a unique capability for
discovering novel molecules that modulate historically undruggable or challenging GPCRs.
Our integrated discovery platform includes 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
are generating a broad pipeline of drug candidates for serious CNS and metabolic
disorders, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, autism,
anxiety & depression, chronic insomnia, addiction and diabetes. For more information,
please visit http://www.heptares.com.


        1) Mason, J.S., et al., New Insights from Structural Biology into the
          Druggability of G Protein-coupled Receptors. Trends Pharmacol. Sci. 2012,
          [http://www.cell.com/trends/pharmacological-sciences/abstract/S0165-6147(12)00031-4 ]
        2) Congreve, M. et al. Discovery of 1,2,4-Triazine Derivatives as Adenosine A2A
          Antagonists using Structure Based Drug Design. J. Med. Chem. 2012, 55 (5):1898-19034

        Contact Information

        Citigate Dewe Rogerson (for Heptares)
        Mark Swallow, Chris Gardner

        Heptares Therapeutics Ltd

        Malcolm Weir, Chief Executive Officer (UK)

        Dan Grau, President (USA)

SOURCE Heptares Therapeutics

Source: PR Newswire