Phthalimide conjugation as a strategy for in vivo target protein degradation

GE Winter, DL Buckley, J Paulk, JM Roberts, A Souza… - Science, 2015 - science.org
GE Winter, DL Buckley, J Paulk, JM Roberts, A Souza, S Dhe-Paganon, JE Bradner
Science, 2015science.org
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 …
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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