Abstract

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 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
diverse libraries of 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
rapidly identify key peptide-target interactions of therapeutic interest, which
we then use as a basis to design small-molecule inhibitors.

We have tested the feasibility of this approach in several disease
models (KRAS^G12V and PTEN ^-/- synthetic lethality,
antigen presentation, Hippo Signalling, ..) and are now seeking key academic
partners to extend the application of this technology and further develop novel
targets resulting from PROTEINi screens. 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.