Phthalimide conjugation as a strategy for in vivo target protein degradation

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Science  19 Jun 2015:
Vol. 348, Issue 6241, pp. 1376-1381
DOI: 10.1126/science.aab1433

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A degrading game plan for cancer therapy

Certain classes of proteins that contribute to cancer development are challenging to target therapeutically. Winter et al. devised a chemical strategy that, in principle, permits the selective degradation of any protein of interest. The strategy involves chemically attaching a ligand known to bind the desired protein to another molecule that hijacks an enzyme whose function is to direct proteins to the cell's protein degradation machinery. In a proof-of-concept study, they demonstrated selective degradation of a transcriptional coactivator called bromodomain-containing protein 4 and delayed the progression of leukemia in mice.

Science, this issue p. 1376


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.

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