Heptares Therapeutics Ltd, the drug discovery company focused on G-protein-coupled receptor (GPCR) targets, provides a positive update on the progress it has made in the discovery of novel therapeutic leads against important GPCR targets.
Since its founding in 2007, Heptares has established an integrated drug discovery capability around its StaR (stabilised receptor) technology platform and now employs more than 40 people at its fully equipped research facilities at BioPark.
Heptares’ StaR technology1 enables its scientists to stabilise GPCRs in functionally relevant conformations that retain their drug-binding characteristics. Subsequently, the Company has shown that these StaRs can be used with powerful but hitherto unavailable discovery techniques, including X-ray structure-based design, receptor binding kinetics analysis, fragment screening, and antibody generation.
Heptares has also developed a surface plasmon resonance (SPR)-based method for 3D determination of compound binding modes, called Biophysical Mapping, which enables the rapid and timely application of structural information to medicinal chemistry.
To date, Heptares has created more than 20 StaRs to more than 12 validated GPCR targets. The Company is advancing multiple discovery programmes in CNS, metabolic and cancer therapeutic areas, and has used its StaR-based drug discovery platform to generate hit and lead series against five GPCRs, including a highly intractable peptide receptor; it has in-house X-ray structures of three of these targets, as well as multiple co-structures with ligands from its chemistry programmes. To date all proteins progressed to structural studies have readily yielded diffracting crystals/structures. This progress demonstrates the industrial robustness and reproducibility of StaR technology.
Heptares’ most advanced programme is focused on the adenosine A2A receptor, which is a clinically validated target for the treatment of Parkinson’s disease. In this programme, Heptares identified by virtual screening and in-house structure-based design a series of potent and selective small molecule antagonists from which a lead candidate is currently being progressed to preclinical development. The Company is currently looking to out-license this programme, having successfully advanced it to this stage from initiation in only 18 months, reflecting the power and efficiency of its approach.
In addition, Heptares has recognized the huge potential of its StaRs for generating monoclonal antibodies against GPCRs, which previously has been difficult owing to their intractability and instability. Heptares discusses this and other approaches, as well as reviewing progress made in identifying and developing functional therapeutic antibodies for the treatment of a wide range of chronic diseases, in a recent article published in MAbs2.
“Heptares’ StaR platform is uniquely capable of exploiting the tremendous potential synergy between two proven drug discovery paradigms that otherwise sit apart, namely the GPCR target superfamily and structure-based design technology,” said Malcolm Weir, Heptares’ CEO. “Increasingly, pharmaceutical companies are looking for novel pipeline compounds with reduced risk of attrition, particularly to poorly tractable targets. We believe that the high quality drug leads Heptares is developing to such targets in the areas of CNS, metabolic disease, cognition and cancer, will be of great interest as we advance our partnering discussions.”
GPCRs are the single most important family of drug targets in the human body, but because of their inherent instability they are refractory to structural studies and biochemical screening. StaR technology enables the engineering of stabilised GPCRs, making them amenable to these vital drug discovery approaches. There are many clinically relevant GPCR targets across a wide range of therapeutic areas where discovery is advancing slowly and for which structural information, novel screening approaches and potential antibody therapeutics would greatly enhance progress.
Reference:
1. The properties of thermostabilised G protein-coupled receptors (StaRs) and their use in drug discovery. Robertson, N. et al. Neuropharmacology (2010).
2. Therapeutic antibodies directed at G protein-coupled receptors. Hutchings, C.J., Koglin, M. and Marshall, F.H. mABs (2010) Vol.2 (Nov/Dec) Issue 6, 594-606
Heptares Therapeutics Ltd
