The potential of protein degradation

Most scientists aren’t in the business of creating new words. Especially chemists and biologists, who stick to a vernacular centered on proteins, molecules and genomes.

But Anil Vasudevan isn’t your typical scientist, and neither are the people on his team within AbbVie’s discovery science group.

Not only have they coined a new term – degradomers – they’re leading the charge to explore how this approach to degrading proteins could eventually help patients with debilitating diseases like rare cancers, immunological conditions and even Parkinson’s and Alzheimer’s diseases.

Degradomers are molecules that have the ability to degrade proteins within cells, says Vasudevan, Ph.D., senior director, discovery platform technologies, AbbVie, who heads global degradomer effort at AbbVie.

They represent a new approach in which scientists generate molecules (degradomers) that hijack the body’s natural system of turning over proteins and carrying them to the trash chute.

Scientists have long relied on one method to impact proteins in cells and treat diseases – inhibiting their function by binding to a specific site.

Protein degradation does something else entirely, says Vasudevan, which is to degrade the desired protein from the system. This approach allows scientists to target a larger part of the human proteome, since degradomers can attach anywhere on a protein and not just a certain site.

Protein degradation has potential in many disease areas, including oncology, immunology and neurology by aiming to selectively eliminating disease associated proteins, says Steve Elmore, Ph.D., vice president, drug discovery science & technology, AbbVie.

“Harnessing the potential of targeted protein degradation unlocks a whole new world for us as scientists, and also for the people with conditions and diseases many thought were untreatable,” Elmore says.

Understanding the potential of protein degradation, Vasudevan and his group began conducting initial experiments in the lab. Violeta Marin, Ph.D., senior scientist, discovery platform technologies, recalls going to Vasudevan’s office along with another colleague Aleksandra Baranczak, Ph.D., in the early days and brainstorming around potential approaches on the whiteboard.

A chemical biologist by trade, she began thinking through how to use chemical matter and bring the theory to life, deriving the “rules” of protein degradation.

Specialists were brought in to help, including Justin Reitsma, Ph.D., senior scientist, discovery platform technologies, AbbVie. His job is to understand the biology behind the technology, which has manifested into a two-year process to identify ligases, or the enzymes that mediate protein degradation, that would work best to hijack.

“We’re beginning to understand how transformative this science can be, with the classic way to treat disease historically limited to about 15 percent of the genome,” Reitsma says. “I think targeted protein degradation represents part of the future of medicine.”

While AbbVie’s protein degradation work is ongoing, the team is staying focused on the potential impact for people battling tough-to-treat diseases.

“We like to think that one day, our work together will make a difference in somebody’s life,” Marin says.