A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos

J Med Chem. 2018 Jan 25;61(2):535-542. doi: 10.1021/acs.jmedchem.6b01921. Epub 2017 Apr 20.

Abstract

The drugs lenalidomide and pomalidomide bind to the protein cereblon, directing the CRL4-CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation. Here we describe CC-220 (compound 6), a cereblon modulator in clinical development for systemic lupus erythematosis and relapsed/refractory multiple myeloma. Compound 6 binds cereblon with a higher affinity than lenalidomide or pomalidomide. Consistent with this, the cellular degradation of Ikaros and Aiolos is more potent and the extent of substrate depletion is greater. The crystal structure of cereblon in complex with DDB1 and compound 6 reveals that the increase in potency correlates with increased contacts between compound 6 and cereblon away from the modeled binding site for Ikaros/Aiolos. These results describe a new cereblon modulator which achieves greater substrate degradation via tighter binding to the cereblon E3 ligase and provides an example of the effect of E3 ligase binding affinity with relevance to other drug discovery efforts in targeted protein degradation.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism
  • Fluorescence Resonance Energy Transfer
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / metabolism
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Ikaros Transcription Factor / metabolism*
  • Lenalidomide / chemistry
  • Lenalidomide / metabolism
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism
  • Peptide Hydrolases / chemistry*
  • Peptide Hydrolases / metabolism*
  • Protein Binding
  • Proteolysis / drug effects*
  • Ubiquitin-Protein Ligases

Substances

  • Adaptor Proteins, Signal Transducing
  • CRBN protein, human
  • DDB1 protein, human
  • DNA-Binding Proteins
  • Heterocyclic Compounds, 4 or More Rings
  • IKZF1 protein, human
  • IKZF3 protein, human
  • Ikaros Transcription Factor
  • iberdomide
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases
  • Lenalidomide