US EPA

7416515 

Journal Article 

Inhibitor mediated protein degradation 

Long, MJ; Gollapalli, DR; Hedstrom, L; , 

2012 

Yes 

Chemistry and Biology
ISSN: 1074-5521 

CELL PRESS 

CAMBRIDGE 

19 

5 

629-637 

English 

22633414 

10.1016/j.chembiol.2012.04.008 

WOS:000304794600014 

https://linkinghub.elsevier.com/retrieve/pii/S1074552112001391
Exit
 

The discovery of drugs that cause the degradation of their target proteins has been largely serendipitous. Here we report that the tert-butyl carbamate-protected arginine (Boc(3)Arg) moiety provides a general strategy for the design of degradation-inducing inhibitors. The covalent inactivators ethacrynic acid and thiobenzofurazan cause the specific degradation of glutathione-S-transferase when linked to Boc(3)Arg. Similarly, the degradation of dihydrofolate reductase is induced when cells are treated with the noncovalent inhibitor trimethoprim linked to Boc(3)Arg. Degradation is rapid and robust, with 30%-80% of these abundant target proteins consumed within 1.3-5 hr. The proteasome is required for Boc(3)Arg-mediated degradation, but ATP is not necessary and the ubiquitin pathways do not appear to be involved. These results suggest that the Boc(3)Arg moiety may provide a general strategy to construct inhibitors that induce targeted protein degradation. 

arginine derivative; benzofurazan derivative; dihydrofolate reductase; etacrynic acid; glutathione transferase; proteasome; trimethoprim; ubiquitin; animal cell; article; cell lysate; cell viability; controlled study; enzyme synthesis; Escherichia coli; flow cytometry; nonhuman; protein degradation; protein expression; protein targeting; signal transduction; ubiquitination; Drug Design; Glutathione Transferase; HeLa Cells; Humans; Phenylcarbamates; Proteasome Endopeptidase Complex; Proteolysis; Tetrahydrofolate Dehydrogenase; Ubiquitin