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Targeted Protein Degradation

Selectively targeting the elimination of disease-causing proteins by using the body’s own degradation machinery

IN BRIEF

Targeted protein degradation (TPD) is a fast-growing area of cancer drug research attracting significant interest from some of the world’s largest pharmaceutical companies. That’s because protein degraders have significant potential advantages over other classes of cancer treatments, including

  • The ability to target previously undruggable cancer-promoting proteins
  • Overcoming drug resistance to better treat advanced disease
  • Requiring lower drug doses to produce therapeutic effects

TPD works by causing degradation, or elimination, of cancer-promoting proteins. Essentially, proteins that are known to cause cancer are selectively targeted and eliminated. This prevents cancer progression and can lead to meaningful therapeutic benefits for patients.

IN DEPTH

Protein turnover is normal for all living cells. The cell has developed its own degradation system, called the ubiquitin-proteasome system. Ubiquitin is a protein that flags other proteins so that the body’s protein degraders, proteasomes, can recognize and degrade them. E3 ligases are enzymes that help kickstart protein degradation.

Targeted Protein Degradation (TPD)

Small molecule degraders trigger protein degradation by bringing together an E3 ligase and a protein of interest, as shown in the figure below.

First, cancer-promoting protein is far from an E3 ligase. Second, molecular glue compounds (drug) bring target protein close to the E3 ligase. Third, target protein is flagged with Ub. Fourth, cancer-promoting protein is recognized and degraded. Drug is recycled.

The two most commonly studied small molecule protein degraders are molecular glues and PROTACs (PROteolysis Targeting Chimeras). Both can be engineered to have different targets, depending on the cancer of interest. Salarius is focused on developing novel molecular glue protein degraders.

Targeting Transcription Factors for Cancer Therapy

If the genome is like a cookbook, transcription factors are the bookmarks the body uses to locate a specific recipe. Transcription factors anchor onto DNA and interact with proteins to alter the chromatin and influence gene expression.

Gene expression is a dynamic process involving transcription factors binding to recognizable DNA sequences and interacting with 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. However, transcription factors can be difficult to target, because unlike enzymes, they lack a clear site where small molecule inhibitors can adhere and inhibit the protein’s cancer-promoting activity.

Fortunately, scientific advances have helped make transcription factors go from undruggable to druggable. TPD is a way to selectively target and eliminate disease-causing transcription factors.