Targeted Degradation of Proteins by PROTACs

Abstract

In recent years, small interference RNAs (siRNAs) have greatly enhanced our understanding of protein functions by allowing knockdown of targeted proteins at the mRNA level. Similarly, in an effort to achieve degradation of targeted proteins at the post‐translational level, chimeric small molecules called “PROTACs” (PROteolysis TArgeting Chimeric molecules) have been developed. The PROTAC approach utilizes chimeric small molecules which recruit targeted proteins to the ubiquitin‐proteasome pathway, a major intracellular protein degradation system. Unlike conventional small molecules that bind to protein and inhibit its function, the PROTAC approach induces destruction of target protein via the ubiquitin‐proteasome system. This article presents a typical strategy for PROTAC design and preparation and biological characterization. Curr. Protoc. Chem Biol. 2:71‐87. © 2010 by John Wiley & Sons, Inc.

Impact of linker length on the activity of PROTACs

“…16 Recently, PROTACs have been investigated as potential therapeutic agents that target disease-promoting proteins for degradation. 17–18 …”

“…16 Recently, PROTACs have been investigated as potential therapeutic agents that target disease-promoting proteins for degradation. 17,18 While the PROTAC containing an E3 ligase recognizing pentapeptide residue has been shown to be cell-permeable and effective at inducing the degradation of target proteins, 8,9,13 its bioavailability and permeability still need to be addressed for the broad application of the PROTAC approach. In this regard, a polyarginine tail was attached to PROTACs to enhance cell permeability.…”

PROTAC-Induced Proteolytic Targeting

“…(2). Depending on the selected ligand and E3 ligase recognition motif, different sets of chemicals will be required.…”

“…The same E3 ligase recognition motif can be attached to a variety of small molecule ligands, thereby generalizing this approach to a broad spectrum of proteins. By inducing proteolytic degradation of their target proteins, PROTACs represent useful tools for both the elucidation of protein function as well as therapeutic applications (2, 3). For example, PROTAC-induced degradation of a particular protein followed by an investigation of the associated phenotypic changes can provide valuable information about the function of that protein.…”

“…The poor cell permeability of the first generation PROTACs was significantly improved by adopting a HIF-1α peptide fragment as an E3 ubiquitin ligase recognition motif in the design of the second generation PROTACs (5-7). So far, androgen receptor (AR) (8) and estrogen receptor (ER) targeting PROTACs (9-11) have been developed, demonstrating the potential applications of these molecules in the treatment of prostate and breast cancers (12, 13) (2, 8). In addition, PROTACs targeting methionine aminopeptidase-2 (MetAP-2) (4), the aryl hydrocarbon receptor (14, 15), and cellular retinoic acid binding proteins (CRABPs) (16) have also been developed.…”