Rick Ewing, Vice President & Head of Chemistry, Rapafusyn Pharmaceuticals, discussed non-degrading molecular glues. Rapafusyn Pharmaceuticals is seeking to repurpose its platform to go beyond mTOR and calcineurin and target the hard-to-drug proteome.
Ewing is looking to go after hard-to-drug targets, and one of the proteins that the company uses in the inhibition mechanism is FKBP12, which resides solely in the cytosol. As an intracellular protein, scientists can target proteins that are fully in the cytosol, covering up to approximately 74% of the proteome.
Pharmaceuticals have a series of macrocycle molecules, and they have a portion that can engage a target protein. By bringing together two proteins that don’t usually reside near each other in close proximity, three key drug properties emerge. The first one is high potency, which results from new protein-protein interactions. Secondly, there is very high selectivity, and finally, there are slow-rate kinetics. Ewing demonstrated all three of these attributes in the hits.
Synthetic challenges present problems for advancing rapamycin. Ewing revealed that his team uses modular macrocycle libraries and AI-driven modelling to predict target compatibility. The platform is based on macrocycles and how the synthetically complex portions of rapamycin can be repurposed.
Ewing explained how the team overcame the synthetic challenges of rapamycin by using modular amino acid units and solid-phase chemistry to construct diverse DNA-encoded libraries (DELs). Ewing commented that the platform achieved a high hit rate (7 for 7 in recent screens) and rapid expansion into diverse target classes.
The platform yielded high cell permeability (96% of tested molecules) and promising selectivity, though bioavailability remains a challenge, with ongoing efforts to optimize this property. Finally, the company has identified selective, potent molecules for targets in the TNFα pathway. Additionally, Rapafusyn is advancing a compound targeting SLC ENT1 toward IND-enabling studies.
