Targeted protein degradation is a promising new way to eliminate toxic or disease-associated targets from cells. Using the cell’s own destruction machinery, new medicines are being developed that allow us to overcome many of the traditional hurdles of drug discovery.
Cells have evolved elegant and efficient protein homeostasis mechanisms which use short chains of ubiquitin to tag other proteins for destruction by the proteasome.
E3 ligases are the crucial mediators of this activity, as together with E1 and E2 enzymes they add the ubiquitin tag to disease-associated proteins, marking them for destruction. Degrader-based drugs (including bivalent degraders like PROTACs) exploit this remarkable process by recruiting E3 ligases to specific target proteins, eliminating them from cells in a highly efficient catalytic process.
This form of induced proximity has numerous advantages over traditional inhibitor drugs and is poised to revolutionise the treatment of a wide variety of diseases. Degraders are a key tool in the Drugging the Undruggable® mission as they can be developed to target almost any protein, including those considered for many years to be otherwise “undruggable”. The targets are removed from cells, rather than just inhibited and the activity of the degrader drugs is catalytic, meaning traditional rules of development and stoichiometry are not usually applicable.
Much of the recent success in degrader development has been dependent on a very small number of E3 ligases (CRBN, VHL, KEAP1 etc). At PhoreMost we are discovering the next-generation of targeted protein degradation molecules. Our SITESEEEKER® Degrader Discovery Platform has been deployed to identify completely new E3 ligases with optimised properties. This allows us to find the right ligase for the right protein target and to empower our drug discovery with selectivity, specificity and functional validation for degrader drug development.
This incredible modality holds enormous promise for new therapies. PhoreMost’s platform has the ability to unlock its full potential and capitalise on this crucial new tool in our mission.
Molecular glues are an emerging class of innovative drug that provide a new way to attack disease-associated proteins. Similar to bivalent degraders like PROTACs, molecular glue degraders (MGDs) are also able to exploit the cell’s proteostasis mechanisms. They achieve this by inducing close proximity between a target protein and an effector protein, like an E3 ligase – gluing them together.
An important advantage of molecular glue degraders is that they are much smaller, more traditional molecules with a clearer route to overcome the translational steps of drug discovery. MGDs have so far only been discovered by serendipity and the principles to design them have remained elusive.
To address this challenge we have developed GlueSEEKER™.
This unique and proprietary new technology uses vast insertional libraries to create a massive diversity of surface-edited E3 ligase variants. Phenotypic screening is then used to identify the specific and precise blueprints for molecular glue activity, integrating deep computational approaches with novel biological discovery. We can apply our approach to find completely new molecular glue design space by inducing the degradation of nearly any nominated neosubstrate and ligase pair and drastically expand the scope for this important new modality. With our GlueSEEKER® technology we aim to systematically unblock MGD discovery to bring new precision medicines to fruition faster.
Our revolutionary SITESEEKER® platform uses massively high-throughput screening of PROTEINi® libraries to perturb disease biology in new and unanticipated ways.
PROTEINi® are genetically-encoded micro-proteins, computationally programmed to optimise bio-activity and maximise the diversity in our proprietary libraries.
We use human cellular assays to model disease biology with high fidelity and screen with our hyper-diverse PROTEINi® libraries. We can identify novel drug targets and unanticipated new drug pockets to inform new drug design and to enable the development of new medicines across disease areas.
| Target ID | Discovery | Preclinical | Phase 1 |
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Undisclosed Targeted Protein Degradation, E3 ligase (multiple targets) |
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SITESEEKER® Targeted Protein Degradation / Oncology (multiple Target ID programmes) |
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We are always happy to discuss exciting new opportunities to partner with us and are open to different collaboration models which meet a shared ambition. If you would like to understand more about our capabilities and opportunities to collaborate, please get in touch.
PLK Oncology, solid tumours