A patent review of von Hippel-Lindau (VHL)-recruiting chemical matter: E3 Ligase Ligands for PROTACs and targeted protein degradation (2019-present)

Introduction: The von Hippel-Lindau (VHL) E3 ubiquitin ligase has seen extensive research due to its involvement in the ubiquitin proteasome system and role as a tumour suppressor within the hypoxia signalling pathway. VHL has become an attractive target for proteolysis targeting chimeras (PROTACs), bifunctional molecules that can induce degradation of neo-substrate proteins. The development of VHL inhibitors and PROTACs has seen rapid development since disclosure of the first non-peptidic VHL ligand (2012).

Areas Covered: Due to the demand for more diverse and sophisticated VHL ligands that can be applied to PROTACs, the number of patents disclosed has risen significantly in the past 5 years. Herein, the wide range of VHL modifications that have been patented since 2019 are covered. Specifically, any new or unique chemical modification to established VHL ligands or PROTACs will be discussed.

Expert Opinion: The VHL chemical space continues to expand within the patent literature. There are exciting new modifications that can enhance the physiochemical properties of VHL PROTACs and other alterations can improve the affinity of the VHL ligand itself. Further optimisation of the VHL chemical space will no doubt lead to the development of more VHL-based therapies and clinical candidates.