GPCR Drug Discovery | GPCRs

A Major Commercial Opportunity

The GPCR superfamily is the largest and single most important family of drug targets in the human body. It plays a central role in many biological processes and is linked to a wide range of disease areas. GPCRs are expressed in every type of cell in the body where their function is to transmit signals from outside the cell across the membrane to signalling pathways within the cell, between cells and between organ systems.

There are over 375 GPCRs encoded in the human genome, of which 225 have known ligands and 150 are orphan targets. GPCRs are the site of action of 25-30% of current drugs. Six of the top ten and 60 of the top 200 best-selling drugs in the US in 2010 target GPCRs, generating multi-billion dollar sales annually.

Drug discovery targeting GPCRs remains challenging, however. In contrast to classes of soluble protein drug targets, such as kinases and proteases, the understanding of GPCRs has been severely hampered by the lack of structural and mechanistic knowledge and an understanding of how compounds interact with them. This has resulted in a general lack of quality GPCR drug leads advancing through pharma pipelines, high failure rates and no successful NCEs to multiple validated high-value targets.

What structural information there is strongly suggests that GPCRs are intrinsically druggable with small molecules or biologics. The overriding problem is that GPCRs are very unstable and lose their highly organised structure and activity when taken out of the cell membrane. Until recently, this has prevented the production of stable, properly folded protein to which contemporary structure-based drug discovery (SBDD) approaches can be applied.

At Heptares, we believe that our unique, integrated SBDD platform can overcome these hurdles and address this major opportunity both for the generation of small molecules and therapeutic antibodies targeting challenging or previously undruggable GPCRs.

Structure of GPCR thermostabilised in the agonist conformation and in complex with endogenous agonist ligand (grey). Critical residues involved in ligand binding highlighted in magenta stick representation; contacts with the receptor shown as dashed red lines.

© 2012-2017 Heptares Therapeutics