Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 22; pp. 5904 - 5908
• Main Authors: Schneekloth, Ashley R., Pucheault, Mathieu, Tae, Hyun Seop, Crews, Craig M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.11.2008; Elsevier
• Subjects: Antineoplastic agents; Biological and medical sciences; Blotting, Western; Cell Line, Tumor; Cell Membrane Permeability; Cell Proliferation - drug effects; Cell Survival; Chemical inducers of dimerization; Dimer; General aspects; Humans; Imidazoles - chemistry; Indicators and Reagents; Medical sciences; Nutlin; Pharmacology. Drug treatments; Piperazines - chemistry; PROTAC; Proteasome; Protein degradation; Proteins - chemistry; Proteins - metabolism; Proteomics - methods; Receptors, Androgen - metabolism; Synthesis; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - metabolism; Protein degradation; Synthesis; Nutlin; PROTAC; Chemical inducers of dimerization; Dimer; Proteasome; Multicatalytic endopeptidase complex; Peptides; Enzyme; Ligand; Enzymatic hydrolysis; Imidazoline derivatives; Oligomer; Biological activity; Ethylene oxide polymer; Peptidases; Androgen receptor; selective androgen receptor modulator; Hydrolases; Small molecule; Chemical synthesis; Non steroid compound
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.07.114

We have developed a heterobifunctional all-small molecule PROTAC (PROteolysis TArgeting Chimera) capable of inducing proteasomal degradation of the androgen receptor. This cell permeable PROTAC consists of a non-steroidal androgen receptor ligand (SARM) and the MDM2 ligand known as nutlin, connected by a PEG-based linker. The SARM–nutlin PROTAC recruits the androgen receptor to MDM2, which functions as an E3 ubiquitin ligase. This leads to the ubiquitination of the androgen receptor, and its subsequent degradation by the proteasome. Upon treatment of HeLa cells with 10 μM PROTAC for 7 h, we were able to observe a decrease in androgen receptor levels. This degradation is proteasome dependent, as it is mitigated in cells pre-treated with 10 μM epoxomicin, a specific proteasome inhibitor. These results have implications for the potential study and treatment of various cancers with increased androgen receptor levels.