In the postgenomic era, opportunities are rich for large-scale, omics approaches for target discovery. Gene editing technologies have significantly improved the landscape for drug development, but blind spots in the reach of these tools are now starting to become apparent. Programme failure due to poor druggabilty profiles is a common theme and progressing new undruggable targets without due support is still perceived as an untenable risk. An ability to modulate the nuances of biological function in high throughput is crucial to adequately probe the druggable space for any disease pathophysiology, and crude on/off perturbation tools are rarely able to screen with this degree of sensitivity. Without such improved tools, the substantial efforts in unbiased drug target ID are likely to yield a pool of promising and yet unactionable candidates.
To fulfil this critical need in drug discovery, we have developed SITESEEKER®, a novel screening technology operating at a substantially greater magnitude of complexity than extant screening platforms. Our unique approach exploits protein interference (or PROTEINi), targeting diseases with computationally-derived coded peptide fragments, evolutionarily enriched for function that can enact precise phenotypic perturbations. The use of a peptide-based element in the context of a functional genomic screen allows for the pre-discovery of the mechanisms for drug development in addition to the ID of new phenotypically tractable targets and significantly truncates the path from target ID to drug development.
We have applied PROTEINi screening in several new areas in serious need of new clinical assets, uncovering new and unprecedented targets and drugs now in late stages of pre-clinical development. In particular, we have deployed SITESEEKER to the challenges of new E3 ligase discovery towards the pursuit of new bifunctional degrader molecules, capable of modulating otherwise undruggable targets. Our cache of novel E3 ligase ligands are active against numerous therapeutic targets and showcase the breadth of proteome space yet to explore in this critical field. We have used combinatorial CRISPR-based screening to unpick the functional dependencies of each degrading PROTEINi and map novel ligands to their cognate E3 ligase. Eight such ligases have progressed through to the early stages of small molecule development, yielding several series primed for development as either bifunctional degraders or monovalent molecular glues. Our SITESEEKER platform is therefore uniquely positioned to dramatically decrease the time taken for new molecules to reach the clinic and positively impact patient outcomes.