GPCRs have proven to be a valuable target family for drug discovery and development with more than 30% of marketed drugs acting through this receptor superfamily. However, numerous GPCR members remain challenging with no selective and druggable ligands being successfully developed. For these difficult targets, novel strategies consisting in developing allosteric modulators or biased ligands (BLs) are now emerging. Indeed, all GPCR agonists do not always uniformly activate all signalling pathways mediated by a given receptor. BLs therefore constitute a novel approach to more selectively activate a receptor for the development of safer drug candidates. This concept of ligand bias, also referred to as functional selectivity, has now been validated in vitro and in vivo, and several GPCR BLs are currently under clinical investigations. Despite these promising features, uncovering and profiling BLs still remains challenging as no specific technology has been proposed for this task. Cell-system dependency of the multiple functional analyses for instance makes it difficult to guide medicinal chemists in their optimization programs toward active BLs. To meet this expectation, the dedicated BioSens-All� technology was generated. BioSens-All� consists in a set of multiple biosensors each engineered to follow one specific functional pathway. The parallel characterization of GPCR orthosteric or allosteric ligands with theses biosensors, in a homogenous format, enables the generation of signalling signatures and consistent comparative data for chemists. This poster will present and exemplify how BioSens-All� can be used to support medicinal chemists in their quest for GPCR biased ligands.

BioSens-All�: Anew technology dedicated to GPCR biased ligand drug discovery

248th National Meeting (2014)

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