Protacs for treatment of cancer

Abstract

Protein degradation is the cell's mechanism of eliminating misfolded or unwanted proteins. The pathway by which proteins are degraded occurs through the ubiquitin-proteasome system. Ubiquitin is a small 9-kD (kDa) protein that is attached to proteins. A minimum of four ubiquitins are required for proteins to be recognized by the degradation machinery, known as the 26S proteasome. Defects in ubiquitination have been identified in a number of diseases, including cancer, neurodegenerative diseases, and metabolic disorders. We sought to exploit the delicate balance between protein synthesis and degradation to treat cancer by designing a chimeric molecule, known as Protac (Proteolysis Targeting Chimeric molecule). Protacs are heterobifunctional nanomolecules that are approximately 10 nm in size and can recruit proteins that cause cancer to the ubiquitin-proteasome machinery for degradation. In this review, we discuss the development of this novel technology for the treatment of cancer.

Figure 1

Ubiquitin Proteasome System. Adapted from Heuze ML et al. 2008 Blood Cells Mol Dis 40:200–210. Copyright © 2007 Elsevier Inc, with permission.

Figure 2

Protac can theoretically target any protein for ubiquitination and degradation. In this case, the protein is recruited to the SCF^β-TRCP E3 ubiquitin ligase, resulting in destruction of the protein target.

Figure 3

Synthesis and chemical structure of a cell permeable Protac with HIF1 peptide and testosterone.

Figure 4

Treatment of 293 human embryonic kidney cells expressing GFP-AR with HIF1-testosterone Protac resulted in degradation of AR.

Figure 5

Potential versatility of Protacs. Any number of ligands or binding partners could be chemically linked to any peptide or small molecule that associates with any E3 ubiquitin ligase to promote the ubiquitination and degradation of a cancer-causing protein. Reprinted from Sakamoto KM et al. 2001 Proc Natl Acad Sci USA 98:8554–8559. Copyright © 2001, The National Academy of Sciences, with permission.