Driving Discovery in Targeted Protein Degradation

Targeted protein degradation (TPD) harnesses the cell’s own ubiquitin-proteasome system to eliminate disease-causing proteins. Bifunctional degraders work by bringing an E3 ligase into proximity with a protein of interest, enabling its ubiquitination and subsequent removal. This approach has expanded therapeutic possibilities by addressing proteins once considered out of reach. With a sharp rise in degrader-focused research and clinical activity, TPD continues to gain traction as a powerful strategy in modern drug discovery. X-Chem is at the forefront, supporting partners as they advance this transformative modality.

The Power of TPD and DELs

X-Chem’s DNA-encoded library (DEL) is perfect for TPD because it takes advantage of this cellular waste disposal system and its dependency on binding affinity, allowing drug developers to target proteins that would be difficult — or impossible — to directly inhibit. DEL-derived ligands for POIs can be easily converted into a heterobifunctional molecule with desired E3 ligand of choice. However, we can also discover novel E3 ligase binders to complement and power your TPD platform. Whether X-Chem is screening for a novel E3 ligand or POI binder, an exact location and vector for the linker position is known through the linker to DNA, which streamlines and saves time in the discovery of degraders. This article on discovering bispecific degraders of ERα further outlines X-Chem’s strategy and success in the TPD space.

TPD

  • Requires binders (not inhibitors) to POI

  • Requires a linker to be tolerated

  • Requires novel E3 engagers

DEL

  • Discovers binders

  • Hits are linked to DNA, so tolerated linker position is known

  • Generates novel E3 engagers (Keap1, DCAF1, CRBN, etc)

Hitting the Mark on Molecular Glue Discovery

Molecular glues (MG) are another class of proximity-dependent molecules that are proving to be a powerful and effective new modality in drug discovery. MGs act as mediators between target proteins, inducing the formation of ternary complexes that can lead to a number of functional outcomes. X-Chem scientists have demonstrated MG selection and confirmed ternary binding by biophysical methods — despite the established elusiveness of glues.

X-Chem’s industry-leading DEL platform and medicinal chemistry expertise are the keys to an expedited drug discovery process and the development of your highly specific TPD-based therapeutic candidate. No matter your modality of interest, we have a solution that suits your needs.