Targeted Protein Degradation

Targeted protein degradation (TPD) involves the selective targeting of disease-causing proteins (oncoproteins) by the body’s own degradation machinery.

TPD is a fast-growing area of cancer drug research that is attracting significant interest from some of the world’s largest pharmaceutical companies because of the potential advantages protein degraders have over other classes of cancer treatments, including the ability to go after previously undruggable cancer-promoting targets, overcoming resistance, and needing less drug quantities to have therapeutic effects.

Protein turnover is a normal part of all living cells. As such, the cell has developed its own degradation system called the ubiquitin-proteasome system. Ubiquitin is a protein that “flags” proteins so that the proteasome, the body’s protein degrader, can recognize the proteins and degrade them. E3 ligases are enzymes that catalyze the addition of ubiquitin to the protein of interest, helping initiate the protein degradation process.

Targeted Protein Degradation (TPD)

Small molecule degraders trigger the protein degradation process by bringing together an E3 Ligase and a protein of interest. There are different types of small molecule protein degraders, the two most studied are molecular glues and PROTACs (PROteolysis Targeting Chimeras). Molecular glues and PROTACs can be engineered to target different oncoproteins, such as transcription factors, depending on the cancer of interest.

Targeting Transcription Factors for Cancer Therapy

Returning to the cookbook analogy in which a person’s genetic code is a recipe and the finished products are proteins, transcription factors are the bookmarks the body uses to get to a specific page, or recipe, in the cookbook. Transcription factors anchor onto DNA and interact with proteins, like epigenetic enzymes, to alter the chromatin and influence gene expression.

In the figure below, a transcription factor binds to a recognizable sequence and will then interact with epigenetic complexes to alter the chromatin architecture to an open or closed state, influencing gene expression and subsequent protein production. Open states are accessible to the body’s transcriptional machinery, i.e., gene expression is turned on, while closed states are not, i.e., gene expression is turned off.

Transcription Factors

Gene expression is a dynamic process involving transcription factors binding to recognizable DNA sequences and interacting with epigenetic protein complexes to change chromatin to an “open” or “closed” state and influence gene expression.

In cancers, transcription factors can act incorrectly to turn on cancer-promoting genes and turn off cancer-suppressing genes. Inhibiting incorrect transcription factor activity is an attractive approach to treating certain cancers. Unfortunately, transcription factors can be difficult to target because, unlike enzymes, they do not contain a clear site for small molecules to adhere to. Fortunately, scientific advances have helped make transcription factors go from undruggable to druggable. Targeted protein degradation is one way to selectively target and eliminate disease causing transcription factors.