Systematic Potency and Property Assessment of VHL Ligands and Implications on PROTAC Design

• Published in: ChemMedChem 2023-04, Vol.18 (8), p.e202200615-n/a
• Main Authors: Krieger, Johannes, Sorrell, Fiona J., Wegener, Ansgar A., Leuthner, Birgitta, Machrouhi‐Porcher, Fouzia, Hecht, Martin, Leibrock, Eva M., Müller, Juliane E., Eisert, Jonathan, Hartung, Ingo V., Schlesiger, Sarah
• Format: Article
• Language: English
• Subjects: Binders; Degradation; ligand design; Ligands; Molecular properties; Nuclear Proteins - metabolism; PROTAC; protein degradation; Proteolysis; structure–activity relationships; Transcription Factors - metabolism; Ubiquitin-Protein Ligases - metabolism; Von Hippel Lindau; Von Hippel-Lindau Tumor Suppressor Protein - metabolism
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202200615

Herein, we describe a systematic SAR‐ and SPR‐investigation of the peptidomimetic hydroxy‐proline based VHL‐ligand VH032, from which most to‐date published VHL‐targeting PROTACs have been derived. This study provides for the first time a consistent data set which allows for direct comparison of structural variations including those which were so far hidden in patent literature. The gained knowledge about improved VHL binders was used to design a small library of highly potent BRD4‐degraders comprising different VHL exit vectors. Newly designed degraders showed favorable molecular properties and significantly improved degradation potency compared to MZ1. Our study describes a systematic evaluation of structure‐activity‐relationships and structure‐property‐relationships for VHL ligand designs. With a particular focus on exit vector analysis, we used our gained knowledge to design a small library of highly potent BRD4‐PROTACs with favorable molecular properties and improved degradation potency compared to MZ1.