From 40 Billion Molecules to Druggable Potential

Targeted protein degradation (TPD) is moving beyond traditional E3 ligases such as CRBN and VHL, with growing interest in identifying novel E3 ligases. To support this evolving landscape, WuXi Biology has established an integrated TPD discovery platform spanning hit identification to candidate optimization.

The platform integrates DNA-encoded library (DEL) screening, fragment-based screening, affinity selection mass spectrometry (ASMS), and virtual screening to efficiently identify target protein ligands and novel E3 ligase binders. The Direct-to-Biology (D2B) approach also accelerates the design-synthesize-test cycle from months to weeks, enabling rapid optimization of bi-functional degraders.

In a recent application, DEL screening across more than 40 billion compounds identified GID4, a substrate receptor of the CTLH E3 ligase complex, as a promising novel E3 ligase for TPD. GID4-based degraders were rapidly optimized using the D2B approach, yielding a 10-fold improvement in BRD4 degradation activity.

As TPD research expands to diverse E3 ligase systems, WuXi Biology’s integrated platform provides the capabilities needed to accelerate ligand discovery and molecular optimization within a broader chemical space.