A 'Click Chemistry Platform' for the Rapid Synthesis of Bispecific Molecules for Inducing Protein Degradation
| Autor: | Christine Sastri, Noelle Javier, Ryan Wurz, J. Russell Lipford, Hannah Dou, Mei-Chu Lo, Victor J. Cee, John McCarter, Ken Dellamaggiore, Dane Mohl |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Ubiquitin-Protein Ligases Drug Evaluation Preclinical Cell Cycle Proteins Protein degradation Ligands 03 medical and health sciences Ubiquitin Drug Discovery Humans Nuclear protein Adaptor Proteins Signal Transducing chemistry.chemical_classification DNA ligase biology Chemistry Cereblon Nuclear Proteins Recombinant Proteins Ubiquitin ligase Cell biology 030104 developmental biology Biochemistry Von Hippel-Lindau Tumor Suppressor Protein Proteolysis biology.protein Molecular Medicine Click Chemistry Target protein Peptides Linker Peptide Hydrolases Transcription Factors |
| Zdroj: | Journal of Medicinal Chemistry. 61:453-461 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b01781 |
| Popis: | Proteolysis targeting chimeras (PROTACs) are bispecific molecules containing a target protein binder and an ubiquitin ligase binder connected by a linker. By recruiting an ubiquitin ligase to a target protein, PROTACs promote ubiquitination and proteasomal degradation of the target protein. The generation of effective PROTACs depends on the nature of the protein/ligase ligand pair, linkage site, linker length, and linker composition, all of which have been difficult to address in a systematic way. Herein, we describe a "click chemistry" approach for the synthesis of PROTACs. We demonstrate the utility of this approach with the bromodomain and extraterminal domain-4 (BRD4) ligand JQ-1 (3) and ligase binders targeting cereblon (CRBN) and Von Hippel-Lindau (VHL) proteins. An AlphaScreen proximity assay was used to determine the ability of PROTACs to form the ternary ligase-PROTAC-target protein complex and a MSD assay to measure cellular degradation of the target protein promoted by PROTACs. |
| Databáze: | OpenAIRE |
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