Proteolysis Targeting Chimeric Molecules

Abstract

Protein degradation is one of the mechanisms employed by the cell for irreversibly destroying proteins. In eukaryotes, ATP-dependent protein degradation in the cytoplasm and nucleus is carried out by the 26S proteasome. Most proteins are targeted to the 26S proteasome by covalent attachment of a multiubiquitin chain. A key component of the enzyme cascade that results in attachment of the multiubiquitin chain to the target or labile protein is the E3 ubiquitin ligase that controls the specificity of the ubiquitination reaction. Defects in ubiquitin-dependent proteolysis have been shown to result in a variety of human diseases, including cancer, neurodegenerative diseases, and metabolic disorders. We have developed a novel approach to target proteins that cause cancer for ubiquitination and degradation. This technology, known as Protac, involves a chimeric molecule that could potentially recruit any cancer-causing protein to an E3 ligase for ubiquitination and subsequent degradation. In this chapter, we describe the development of this technology for cancer therapy.