The Von Hippel-Lindau (VHL) E3 ligase is one of the most widely used protein degradation targets in PROTAC discovery. While VHL-recruiting degraders continue to show significant therapeutic potential, the physicochemical properties of current VHL ligands can present challenges for oral bioavailability. Identifying alternative ligand-efficient binding sites is therefore a key objective in advancing next-generation targeted protein degradation strategies.<\/p>\n\n\n\n
This poster explores how combining complementary fragment screening technologies can accelerate the identification of novel VHL binders and uncover previously unexplored opportunities for PROTAC development. Using Surface Plasmon Resonance (SPR), Spectral Shift (SpS) screening, and X-ray crystallography, researchers screened more than 2,000 fragments against the VHL-Elongin C-Elongin B (VCB) complex to identify and validate promising fragment hits.<\/p>\n\n\n\n
Fragment-based drug discovery offers a powerful approach for uncovering new binding pockets and generating highly ligand-efficient starting points for medicinal chemistry optimization. Through orthogonal screening and follow-up characterization, the study identified 12 fragments with reproducible binding affinities and successfully solved crystal structures for four hits.<\/p>\n\n\n\n
A particularly promising fragment, F4, was found to bind within a previously undescribed pocket on Elongin B. Structural analysis suggests this site remains accessible within the active E3 ligase complex and may provide a novel route for developing alternative VHL-recruiting ligands and PROTAC handles.<\/p>\n\n\n\n