Molecular mechanisms of cereblon-based drugs

Pharmacol Ther. 2019 Oct;202:132-139. doi: 10.1016/j.pharmthera.2019.06.004. Epub 2019 Jun 14.

Abstract

Thalidomide, well known for its potent teratogenicity, has been re-evaluated as a clinically effective drug for the treatment of multiple myeloma. Although the direct target of thalidomide had been unclear until recently, we identified cereblon (CRBN) as a primary direct target of this drug by affinity purification using ferrite glycidyl methacrylate (FG) beads in 2010. CRBN functions as a unique substrate receptor of cullin-RING ligase 4 (CRL4). Various ligands including thalidomide bind to CRBN and alter substrate specificity depending on compound shape, resulting in multiple beneficial effects and/or teratogenicity. Lenalidomide, a thalidomide derivative approved by the US Food and Drug Administration (FDA), induces the degradation of onco-proteins such as Ikaros and casein kinase 1 alpha (CK1α), resulting in anti-cancer effects. Recently, novel CRBN-binding compounds have been developed and their mechanisms of action have been analyzed, including identification of CRBN-related ubiquitin conjugating enzymes (E2s). Moreover, the 3D structure of several CRBN-ligand-substrate complexes has been determined. Ligands were shown to work as a molecular glue between CRBN and its neosubstrate. In addition, investigators have been recently developing CRBN-based proteolysis-targeting chimeras to achieve degradation of proteins of interest. In this review, the molecular mechanisms of classical and new CRBN-based drugs are described, and recent advances in this field are discussed.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Humans
  • Ligands
  • Pharmaceutical Preparations / administration & dosage*
  • Pharmaceutical Preparations / chemistry*
  • Proteolysis

Substances

  • Adaptor Proteins, Signal Transducing
  • Ligands
  • Pharmaceutical Preparations