2. Academic Validation
  3. Systematic Potency and Property Assessment of VHL Ligands and Implications on PROTAC Design

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

  • ChemMedChem. 2023 Apr 17;18(8):e202200615. doi: 10.1002/cmdc.202200615.
Johannes Krieger 1,  Fiona J Sorrell 1,  Ansgar A Wegener 1,  Birgitta Leuthner 1,  Fouzia Machrouhi-Porcher 2,  Martin Hecht 2,  Eva M Leibrock 1,  Juliane E Müller 1,  Jonathan Eisert 1,  Ingo V Hartung 1,  Sarah Schlesiger 1
Affiliations

Affiliations

  • 1 Discovery and Development Technologies, Merck Healthcare KGaA, Frankfurter Straße 250, 64293, Darmstadt, Germany.
  • 2 Site Management Analytics, Merck KGaA, Frankfurter Straße 250, 64293, Darmstadt, Germany.
PMID: 36749883 DOI: 10.1002/cmdc.202200615
Abstract

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.

Keywords

PROTAC; Von Hippel Lindau; ligand design; protein degradation; structure-activity relationships.

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