Targeted protein degradation has moved from a curiosity to a genuine drug discovery strategy in a remarkably short time. PROTACs, molecular glues, and other targeted protein degraders now feature across many oncology and CNS drug discovery programmes, and with that shift has come renewed interest in understanding which E3 ligases are actually worth recruiting.
Alongside cereblon \(CRBN\), Von Hippel-Lindau remains one of the most validated. The structural basis for VHL recruitment is well understood, and there is now an extensive body of structural and co-crystal data. The ligand series that emerged from work at the Ciulli laboratory and others gives medicinal chemists a solid starting point. That said, VHL expression and activity vary across tissues, and tissue-specific ligase activity matters considerably when you are thinking about which targets are tractable and in which disease context. What has become clear from PROTAC campaigns over the last few years is that the linker and the E3 ligand are not passive connectors. They participate in the ternary complex geometry, and small changes to either can dramatically alter degradation efficiency, even when the binary binding affinities of the target and E3 ligase ligands change very little. This means that having access to a range of VHL ligands with different exit vectors and attachment points is not a nice-to-have. It is a practical requirement for running a real structure-activity relationship around the degrader itself. We have expanded our VHL ligand collection with a new set of compounds covering varied linker attachment sites, hydroxylproline configurations, and capping group substitution patterns. These are designed to provide medicinal chemists with more starting points for ternary complex exploration without having to synthesise each variant from scratch. Explore our range of building blocks using the advanced search tools at https://lnkd.in/d2sg35YQ Some wider reading on VHL ligands 1. Impact of Linker Composition on VHL PROTAC Cell Permeability https://lnkd.in/e2PUgTes 2. A patent review of von Hippel-Lindau \(VHL\)-recruiting chemical matter: E3 ligase ligands for PROTACs and targeted protein degradation \(2019–present\) https://lnkd.in/e9R4T-kt 3. Journey of Von Hippel-Lindau \(VHL\) E3 ligase in PROTACs design: From VHL ligands to VHL-based degraders https://lnkd.in/eJJQi8tv