Phthalimide conjugation as a strategy for in vivo target protein degradation

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…

• DR
  Damon Runyon Cancer Research Foundation

  Award: DRG-2196-14
• WL
  William Lawrence and Blanche Hughes Foundation
• NI
  National Institutes of Health

  Awards: P01-CA066996, R01-CA176745