Exploiting ubiquitin ligase cereblon as a target for small-molecule compounds in medicine and chemical biology

Cell Chem Biol. 2021 Jul 15;28(7):987-999. doi: 10.1016/j.chembiol.2021.04.012. Epub 2021 May 24.


Cereblon (CRBN), originally identified as a gene associated with intellectual disability, was identified as primary target of thalidomide. Accumulating evidence has shown that CRBN is a substrate receptor of Cullin Ring E3 ubiquitin ligase 4 (CRL4) containing DDB1, CUL4, and RBX1, which recognizes specific neosubstrates in the presence of thalidomide or its analogs and induces their ubiquitination and proteasomal degradation. A set of small-molecule, CRBN-binding drugs are known as molecular glue degraders because these compounds promote the interaction between CRBN and its neosubstrates. Moreover, CRBN-based proteolysis-targeting chimeras, heterobifunctional molecules hijacking CRBN and inducing degradation of proteins of interest, have emerged as a promising modality in drug development and are being actively investigated. Meanwhile, the original functions and regulations of CRBN are still largely elusive. In this review, we describe key findings surrounding CRBN since its discovery and then discuss a few unanswered issues.

Keywords: cereblon; molecular glue degraders; thalidomide; ubiquitin ligase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Ubiquitin-Protein Ligases / antagonists & inhibitors*
  • Ubiquitin-Protein Ligases / metabolism


  • Adaptor Proteins, Signal Transducing
  • CRBN protein, human
  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Ubiquitin-Protein Ligases