Publication Date:
2015-05-23
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Winter, Georg E -- Buckley, Dennis L -- Paulk, Joshiawa -- Roberts, Justin M -- Souza, Amanda -- Dhe-Paganon, Sirano -- Bradner, James E -- P01 CA066996/CA/NCI NIH HHS/ -- P01-CA066996/CA/NCI NIH HHS/ -- R01-CA176745/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 19;348(6241):1376-81. doi: 10.1126/science.aab1433. Epub 2015 May 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. ; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25999370" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Azepines/chemistry/*pharmacology/therapeutic use
;
Cell Line, Tumor
;
Crystallography, X-Ray
;
Disease Models, Animal
;
*Drug Design
;
Leukemia, Promyelocytic, Acute/drug therapy
;
Ligands
;
Mice
;
Molecular Targeted Therapy
;
Nuclear Proteins/antagonists & inhibitors/chemistry/*metabolism
;
Peptide Hydrolases/*metabolism
;
Phthalimides/*chemistry
;
Protein Stability/drug effects
;
Protein Structure, Tertiary
;
Proteolysis/*drug effects
;
Tacrolimus Binding Protein 1A/metabolism
;
Thalidomide/*analogs & derivatives/chemistry/pharmacology/therapeutic use
;
Transcription Factors/antagonists & inhibitors/chemistry/*metabolism
;
Ubiquitin-Protein Ligases/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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