De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives

J Med Chem. 2019 Jul 25;62(14):6615-6629. doi: 10.1021/acs.jmedchem.9b00454. Epub 2019 Jul 12.


Targeted protein degradation via cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase complex, is an increasingly important strategy in various clinical settings, in which the substrate specificity of CRBN is altered via the binding of small-molecule effectors. To date, such effectors are derived from thalidomide and confer a broad substrate spectrum that is far from being fully characterized. Here, we employed a rational and modular approach to design novel and minimalistic CRBN effectors. In this approach, we took advantage of the binding modes of hydrolyzed metabolites of several thalidomide-derived effectors, which we elucidated via crystallography. These yielded key insights for the optimization of the minimal core binding moiety and its linkage to a chemical moiety that imparts substrate specificity. Based on this scaffold, we present a first active de-novo CRBN effector that is able to degrade the neo-substrate IKZF3 in the cell culture.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Cell Line
  • Drug Design
  • Humans
  • Hydrolysis
  • Ikaros Transcription Factor / metabolism
  • Molecular Docking Simulation
  • Proteolysis / drug effects
  • Thalidomide / analogs & derivatives*
  • Thalidomide / pharmacology*
  • Ubiquitin-Protein Ligases


  • Adaptor Proteins, Signal Transducing
  • CRBN protein, human
  • IKZF3 protein, human
  • Ikaros Transcription Factor
  • Thalidomide
  • Ubiquitin-Protein Ligases