Development of Protacs to Target Cancer-promoting Proteins for Ubiquitination and Degradation

• DOI: 10.1074/mcp.t300009-mcp200
• Publication Date: 2003-10-07T00:14:38Z
• Authors: Kathleen M. Sakamoto; Kyung B. Kim; Rati Verma; Andy Ransick; Bernd Stein; Craig M. Crews; Raymond J. Deshaies
• Keywords: Degradation; Protein Degradation

The proteome contains hundreds of proteins that in theory could be excellent therapeutic targets for the treatment human diseases. However, many these are from functional classes have never been validated as viable candidates development small molecule inhibitors. Thus, to exploit fully potential Human Genome Project advance medicine, there is a need develop generic methods inhibiting protein activity do not rely on target protein's function. We previously demonstrated normally stable protein, methionine aminopeptidase-2 or MetAP-2, artificially targeted an Skp1-Cullin-F-box (SCF) ubiquitin ligase complex ubiquitination and degradation through chimeric bridging Protac (proteolysis targeting molecule). This consisted SCF(beta-TRCP)-binding phosphopeptide derived IkappaBalpha linked ovalicin, which covalently binds MetAP-2. In this study, we employed approach two different proteins, estrogen (ER) androgen (AR) receptors, implicated progression breast prostate cancer, respectively. show here estradiol-based can enforce alpha isoform ER vitro, dihydroxytestosterone-based introduced into cells promotes rapid disappearance AR proteasome-dependent manner. Future improvements technology may yield general treat number diseases, including cancer.