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Published March 31, 2004 | Supplemental Material
Journal Article Open

Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation


Genetic loss of function analysis is a powerful method for the study of protein function. However, some cell biological questions are difficult to address using traditional genetic strategies often due to the lack of appropriate genetic model systems. Here, we present a general strategy for the design and syntheses of molecules capable of inducing the degradation of selected proteins in vivo via the ubiquitin−proteasome pathway. Western blot and fluorometric analyses indicated the loss of two different targets:  green fluorescent protein (GFP) fused with FK506 binding protein (FKBP12) and GFP fused with the androgen receptor (AR), after treatment with PROteolysis TArgeting Chimeric moleculeS (PROTACS) incorporating a FKBP12 ligand and dihydrotestosterone, respectively. These are the first in vivo examples of direct small molecule-induced recruitment of target proteins to the proteasome for degradation upon addition to cultured cells. Moreover, PROTAC-mediated protein degradation offers a general strategy to create "chemical knockouts," thus opening new possibilities for the control of protein function.

Additional Information

© 2004 American Chemical Society. Received 13 October 2003. Published online 6 March 2004. Published in print 1 March 2004. J.S.S. thanks the American Chemical Society, Division of Medicinal Chemistry, and Aventis Pharmaceuticals for a predoctoral fellowship. We would like to thank Charles Sawyers (UCLA) for providing the GFP-AR expression plasmid. We thank John Hines for helpful discussions. This work was supported by the NIH (R21 DK63404 to C.M.C.), UCLA SPORE in Prostate Cancer Research (P50 CA92131 to K.M.S.), CaPCURE (R.J.D., C.M.C., and K.M.S.), Department of Defense (DAMD17-03-1-0220 to K.M.S.), UC BioSTAR Project (01-10232 to K.M.S.), Stein-Oppenheimer Award (K.M.S.), and the Susan G. Komen Breast Cancer Foundation (DISS0201703 to R.J.D.). R.J.D. is an Assistant Investigator of the HHMI.

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Supplemental Material - ja039025zsi20040128_034802.pdf


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