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  2. A "Click Chemistry Platform" for the Rapid Synthesis of Bispecific Molecules for Inducing Protein Degradation

A "Click Chemistry Platform" for the Rapid Synthesis of Bispecific Molecules for Inducing Protein Degradation

  • J Med Chem. 2018 Jan 25;61(2):453-461. doi: 10.1021/acs.jmedchem.6b01781.
Ryan P Wurz Ken Dellamaggiore Hannah Dou 1 Noelle Javier 1 Mei-Chu Lo 1 John D McCarter Dane Mohl Christine Sastri J Russell Lipford Victor J Cee
Affiliations

Affiliation

  • 1 Department of Therapeutic Discovery-Discovery Technologies, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
Abstract

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.

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