What question did this study set out to answer?

To establish a chemical approach for selective target protein degradation in vivo by recruiting the cereblon E3 ubiquitin ligase complex to degrade multidomain proteins such as BRD4.

May 21, 2015Science

Phthalimide conjugation as a strategy for in vivo target protein degradation

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Authors

GWGeorg E. WinterAustrian Academy of Sciences DBDennis L. BuckleyNovartis (China)JPJoshiawa PaulkNovartis (United States)

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Implication

Preclinical study demonstrates selective target protein degradation in leukemic mice, indicating a chemical strategy to pharmacologically target previously undruggable transcription factors.

Key Points

To establish a chemical approach for selective target protein degradation in vivo by recruiting the cereblon E3 ubiquitin ligase complex to degrade multidomain proteins such as BRD4.
Conjugated a competitive BET bromodomain antagonist to a phthalimide moiety to generate the bifunctional molecule dBET1.
Evaluated target protein degradation across in vitro cell models and in vivo mouse models of leukemia.
Synthesized and tested an analogous series of phthalimide-conjugated probes targeting the cytosolic protein FKBP12.
dBET1 triggered selective, cereblon-dependent degradation of BRD4 and BET proteins both in vitro and in vivo.
Administration of dBET1 delayed leukemia progression in leukemic mice compared to baseline disease progression.
Phthalimide conjugation successfully promoted selective degradation of FKBP12, demonstrating the generalizability of the degradation strategy.

Cite This Study

Winter et al. (2015) studied this question.

synapsesocial.com/papers/69d91ce2ccb0bba5a568428e https://doi.org/10.1126/science.aab1433

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Implication

Preclinical study demonstrates selective target protein degradation in leukemic mice, indicating a chemical strategy to pharmacologically target previously undruggable transcription factors.

Phthalimide conjugation as a strategy for in vivo target protein degradation

Discussion

Member takes

Implication

Key Points

Cite This Study

Phthalimide conjugation as a strategy for in vivo target protein degradation

Discussion

Member takes

Implication

Key Points

Cite This Study

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