Objective
Despite an increasing spend in drug development, many diseases remain unaddressed with little hope of finding new treatment options by conventional means. One reason for this is the lack of knowledge regarding which proteins are druggable, and which pockets on the protein surface might be most beneficially targeted by small molecules.
Current methods for discovering new drug targets comprehensively rely on genetic knock-out (CRISPR) or knock-down (RNAi) methods, which work by removing, rather than inhibiting a target, and do not directly query the domain where most small molecule drugs function: the proteome. Therefore, while these techniques can be useful in providing candidate therapeutic target genes, the next step of developing protein-targeting therapies often stalls due to insufficient information on druggability.
In order to address this problem, PhoreMost - a biotech start-up based in Cambridge, UK has developed a phenotypic screening technology called “Protein Interference” (PROTEINi®) that yields both the target’s identity as well as information on available druggable sites within said target. PROTEINi utilises large, diverse libraries of in-silico designed small, self-folding, three-dimensional peptide "shapes", which are expressed in live cells and, much like small molecules, interfere and engage with available pockets on target proteins on a proteome-wide scale. Using pooled NGS-based phenotypic screening formats we identify key peptide-target interactions of therapeutic interest in various disease models, which we then use as a basis to design small-molecule inhibitors.
We have tested the feasibility of this approach in oncology (KRASG12V and PTEN-/- synthetic lethality), immuno-onc (boosting antigen presentation), neuropathology (Autophagy modulation), and several other areas of unmet need and are currently progressing our first small molecules in hit to lead phase.
PhoreMost’s ambition is to promote an alternative, collaborative ethical drug discovery model that strategically combines the diverse array of expertise in academia, small biotech companies and clinical centres, to bring a systematic pipeline of first-in-class drugs more efficiently to market at prices that patients and healthcare systems can afford.
