DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation

Science. 2015 Jun 19;348(6241):1376-81. doi: 10.1126/science.aab1433. Epub 2015 May 21.

Abstract

The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a competitive antagonist of BET bromodomains to a phthalimide moiety to hijack the cereblon E3 ubiquitin ligase complex. The resultant compound, dBET1, induced highly selective cereblon-dependent BET protein degradation in vitro and in vivo and delayed leukemia progression in mice. A second series of probes resulted in selective degradation of the cytosolic protein FKBP12. This chemical strategy for controlling target protein stability may have implications for therapeutically targeting previously intractable proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Azepines / therapeutic use
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Drug Design*
  • Leukemia, Promyelocytic, Acute / drug therapy
  • Ligands
  • Mice
  • Molecular Targeted Therapy
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Peptide Hydrolases / metabolism*
  • Phthalimides / chemistry*
  • Protein Stability / drug effects
  • Protein Structure, Tertiary
  • Proteolysis / drug effects*
  • Tacrolimus Binding Protein 1A / metabolism
  • Thalidomide / analogs & derivatives*
  • Thalidomide / chemistry
  • Thalidomide / pharmacology
  • Thalidomide / therapeutic use
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Azepines
  • BRD4 protein, human
  • CRBN protein, human
  • Cell Cycle Proteins
  • Ligands
  • Nuclear Proteins
  • Phthalimides
  • Transcription Factors
  • dBET1 compound
  • phthalimide
  • Thalidomide
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases
  • Tacrolimus Binding Protein 1A

Associated data

  • PDB/4ZC9