title: DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Georg E
authors.initials: GE
authors.lastname: Winter
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Buckley
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Joshiawa
authors.initials: J
authors.lastname: Paulk
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Roberts
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Souza
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Sirano
authors.initials: S
authors.lastname: Dhe-Paganon
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. james_bradner@dfci.harvard.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D015195:Drug Design; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy; D008024:Ligands; D051379:Mice; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D010797:Phthalimides / Q000737:chemistry*; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D059748:Proteolysis / Q000187:drug effects*; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001381:Azepines; D018797:Cell Cycle Proteins; D008024:Ligands; D009687:Nuclear Proteins; D010447:Peptide Hydrolases; D010797:Phthalimides; D022061:Tacrolimus Binding Protein 1A; D013792:Thalidomide; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C502543:CRBN protein, human; C000599191:dBET1 compound; C037431:phthalimide