GPCR Drug Discovery

Approximately 40 – 50% of currently marketed drugs target GPCRs, so an understanding of the molecular functionality of these receptors is highly clinically and commercially relevant. Despite the success of GPCR drugs, the reality is that many of them have significant levels of unexplained and undesirable side effects. Moreover, only about 10% (40 – 50) of all non-odorant GPCRs have proved to be druggable, with the remainder being seen as an untapped source of targets for next generation GPCR drugs.

The safety and efficacy of GPCR drugs, as with all drugs, are a direct result of the intracellular signalling pathways that they affect.  Historically, GPCR drugs were identified as stimulating or inhibiting discrete G-protein signalling pathways, with beta-arrestin activation viewed simplistically as “desensitising” further receptor stimulation.

It is now known that beta-arrestin pathways have wider roles independent of G-protein pathways.  For example, beta-arrestin activation can block GPCR-mediated apoptosis (cell death). It is now known that some ligands to GPCRs can discretely trigger either, or both G-protein pathways and beta-arrestin pathways. This has given rise to the concept of biased GPCR ligands and drugs.

Dimerix’s approach to GPCR drug discovery takes all the existing knowledge about GPCR signalling, and superimposes on this the paradigm that GPCRs also function as complexes of different GPCRs – called GPCR heteromers.  Importantly, Dimerix proprietary GPCR-HIT platform is the enabling tool allowing both the identification and investigation of GPCR heteromers and their downstream signalling pathways in a ligand-dependent way.

Dimerix is developing the next generation of GPCR heteromer optimized drugs.