Evaluation of the Efficacy of Various Hydrophobic Degrons for PROTAC-Mediated Degradation of the Androgen Receptor

The androgen receptor (AR) pathway is a major contributor to prostate cancer (PC) & tumor growth. Because of this, many therapeutic strategies and drugs attempt to disrupt this pathway to slow or stop tumor growth. The typical solution has been to use an inhibitor, known as an AR antagonist, that binds to the AR to inhibit its function. However, PC cells can often develop resistance to this method of treatment, ignoring the AR antagonists or reversing their role, causing the inhibitor to activate their pathway. Targeted protein degradation is a rapidly growing area in drug design, & has been suggested as another treatment strategy for cancers that become resistant to traditional strategies. One method of targeted protein degradation is hydrophobic tagging: binding the protein to a hydrophobic molecule. This resembles a partially unfolded protein, leading to ubiquitination & activation of cellular protein degradation machinery. One novel method is to use heterobifunctional molecules known as proteolysis targeting chimeras (PROTACs). A PROTAC contains a ligand for the protein of interest (POI) on one side, connected by a linker to a group known to induce degradation, also known as a degron. These PROTACs are highly effective in theory, because they are highly selective, small molecules, & should be capable of eliminating POIs rather than attempting to alter their function. Our research aims to treat PC cells with PROTACs containing an AR antagonist that will selectively bind the AR, attached to various hydrophobic moieties to test their relative effectiveness as degrons. If these hydrophobic moieties are effective degrons, a chemical library of degrons can be established, making it possible to use them in future designs targeting other proteins.