Fragment Screening for VHL Binders & PROTAC Development

The Von Hippel-Lindau (VHL) E3 ligase is one of the most widely used protein degradation targets in PROTAC discovery. However, the limited range of available VHL ligands and their challenging physicochemical properties continue to restrict the development of orally bioavailable VHL-recruiting degraders.

This post explored how fragment-based screening can uncover novel ligand-efficient starting points for VHL ligand discovery. Using Spectral Shift (SpS) technology and the Sygnature Fragment Library, researchers identified previously unknown binders of the VHL-ElonginC-ElonginB (VCB) complex and characterized their binding sites through X-ray crystallography.

Identifying New Opportunities for Targeted Protein Degradation

Fragment-based approached are well suited to discovering novel binding sites and generating high ligand-efficiency starting points for medicinal chemistry optimization. In this study, approximately 1,600 fragments were screened against the VCB complex, leading to the identification of 12 confirmed binders with reproducible affinities. Subsequent competition assays and structural studies revealed binding sites distinct from well-characterized HIF pocket.

Download the poster to learn more about:

• Spectral Shift screening of approximately 1,600 fragments against the VCB complex
• Identification of 12 confirmed fragment hits with reproducible KD values
• Competition assays demonstrating binding outside the HIF interaction site
• X-ray crystallography characterization of four fragment binders
• Discovery of a novel Elongin B binding pocket
• Opportunities to develop new ligand-efficient VHL-recruiting PROTAC handles

From Fragment Hits to Novel PROTAC Handles

Structural analysis identified a particularly promising fragment, F4, binding within a previously unexploited pocket on Elongin B. Unlike known binding sites that overlap with critical protein-protein interaction interfaces, this novel site appears accessible within the active E3 ligase complex and offers a potential avenue for developing alternative VHL-recruiting ligands.

These findings demonstrate how combining fragment screening, biophysical characterization, and structural biology can uncover new opportunities in targeted protein degradation and support the development of next-generation degrader therapeutics.