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Molecular & Cellular Proteomics 2:1350-1358, 2003.
© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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Technology

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

Kathleen M. Sakamoto^,,¶, Kyung B. Kim^||, Rati Verma^,**, Andy Ransick, Bernd Stein, Craig M. Crews and Raymond J. Deshaies^,¶,**

From the Division of Hematology-Oncology, Mattel Children’s Hospital at the University of California Los Angeles, Gwynn Hazen Cherry Memorial Laboratories, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California Los Angeles, and Jonsson Comprehensive Cancer Center, Molecular Biology Institute, Los Angeles, CA 90095-1752, Division of Biology, California Institute of Technology, Pasadena, CA 91125, ^|| Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, ^** Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, Signal Division, Celgene, San Diego, CA 92121, and Department of Molecular, Cellular, and Developmental Biology, Departments of Chemistry and Pharmacology, Yale University, New Haven, CT 06520

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

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