Abstract: Large-scale omics-based approaches for new target discovery have significantly improved the landscape for the development of novel therapeutics. However, blind spots in the reach of tools such as CRISPR and RNAi are now starting to become apparent. Programme failures due to poor target selection are common and significant challenges remain in early drug discovery for targets with limited precedent and/or tractability. To overcome these limitations, we have developed SITESEEKER®, a novel screening technology operating at a substantially greater magnitude of complexity than extant target discovery platforms.
This unique approach exploits protein interference (PROTEINi) to target disease-relevant phenotypes with computationally designed mini-protein species. The use of a peptide-based element in the context of a functional genomic screen allows for the discovery of novel targets that may be missed through traditional gene editing or knockdown approaches. Moreover, PROTEINi can provide valuable mechanistic insights that help to inform, unlock and truncate the path from target ID to drug discovery. We have applied SITESEEKER® in several therapeutic areas, uncovering new and unprecedented targets which are now progressing towards the late stages of pre-clinical development.
Current targeted protein degradation (TPD) modalities, such as PROTACs, are constrained by their heavy reliance on a limited set of target-degrading E3 ligases (principally Cereblon and VHL), and moreover the degree of selectivity (both for disease and target) for degrader mechanisms has not yet been fully understood. Using the SITESEEKER® platform, we describe the discovery and development of novel degrader mechanisms which showcase the breadth of the UPS space yet to be explored in this critical field. We used combinatorial perturbation screening with our leading PROTEINi to unpick the functional dependencies of each degrader and map them to their cognate E3 ligase. To exemplify the approach, we also derive small bifunctional degraders molecules from these unique PROTEINi-E3 interaction maps to enable drug development in the degrader modality. This innovative integrated platform is therefore positioned to rapidly expand the drug discovery landscape in TPD.
