Targeted protein degradation is a rapidly growing research area in drug discovery. One method of targeted protein degradation is hydrophobic tagging: post-translationally modifying or otherwise conjugating the protein to a hydrophobic molecule. This is believed to resemble a partially unfolded protein, leading to ubiquitination and activation of protein degradation machinery. This method has been highly effective for certain proteins, but there has been some difficulty in designing tags to apply to various other proteins. One novel way to work around this could be heterobifunctional molecules known as proteolysis targeting chimeras (PROTACs). A PROTAC contains a ligand for the protein of interest on one side, connected by a linker to a group known to induce degradation, also known as a degron. Our research aims to target the androgen receptor (AR) proteins by using PROTACs to attach various synthetic hydrophobic moieties as degrons to the AR antagonist and test the relative effectiveness of these synthetic hydrophobic degrons. Then, we seek to correlate the degradation efficacy to the properties of the degron. If successful, it could present potential therapeutic options for AR-dependent prostate cancer. More importantly, if these synthetic hydrophobic moieties are effective degrons, it is possible they can be used in future designs targeting other proteins.

Evaluation of synthetic hydrophobic moieties as degrons in PROTAC-mediated degradation of the androgen receptor

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