Selective Target Protein Degradation via Phthalimide Conjugation

By Georg E. Winter, Dennis L. Buckley, Joshiawa Paulk, Justin M. Roberts, Amanda L. Souza, S. Dhe-Paganon, James E. Bradner. Science, 2015

1,045 citations recorded by the source corpus.

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 A chemical strategy that leads to selective destruction of proteins of interest may be a valuable tool for drug development. 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.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5a4c9c8f140190065b8995955f601613b4f53716

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Citations in the corpus

Transcriptional Addiction in Cancer (2017, neutral): “As an example, the general chemical strategy for drug-induced degradation of targeted proteins provides one path to this goal (Figure 6F) (Winter et al., 2015).”
YY1 Is a Structural Regulator of Enhancer-Promoter Loops (2017, positive): “We used an inducible degradation system (Erb et al., 2017; Huang et al., 2017; Winter et al., 2015) to fully deplete YY1 protein levels and measured the impact on gene expression in mESCs genome-wide through RNA sequencing (RNA-seq) analysis (Figures 5A and 5B).”
Proteolysis Targeting Chimeras as Therapeutics and Tools for Biological Discovery (2020, neutral): “…need optimization of their physico-chemical properties for in vivo work, there are many examples of PROTACs functioning in vivo, including mammals (Bondeson et al., 2015; Burslem et al., 2018c; Jain et al., 2019; Nabet et al., 2018; Winter et al., 2015) and non-human primates (Sun et al., 2019).”
Lessons in PROTAC design from selective degradation with a promiscuous warhead (2017, background): “Proteins effectively degraded by PROTACs include RIPK2 and ERRa (Bondeson et al., 2015), BRD4 (Lu et al., 2015; Ohoka et al., 2017; Raina et al., 2016; Winter et al., 2015), BRD9 (Remillard et al., 2017), BCR/Abl and Abl (Lai et al., 2016; Ohoka et al., 2017), and ERa (Ohoka et al., 2017).”