Unlocking the next level of protein degradation

Since the discovery of degradomers – molecules that degrade proteins within cells – AbbVie teams have built their expertise and are now focused on building a broader platform that’s sustainable, repeatable and scalable across different therapeutic areas, according to Vasudevan, Ph.D., our senior director, discovery platform technologies and head of global degradomer efforts.

Early learnings centered on how this new approach of generating molecules (degradomers) could hijack the body’s system of turning over proteins and carrying them to the trash chute, Vasudevan says.

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 has unlocked a whole new world for us as scientists, and also for the people with conditions and diseases many thought were untreatable,” Elmore says. “Our culture of exploration and curiosity has helped us drive forward this work the past several years.”

Understanding the nuances of degradation, including if it truly could be done in a way that could eventually lead to new therapies, represented the first wave of innovation in previous years, Vasudevan says.

As part of this wave, 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 her colleagues in the early days and brainstorming around potential approaches on the whiteboard.

A chemical biologist by trade, she helped establish a path to leverage chemical matter and bring the theory to life, deriving a playbook for protein degradation.

Today, this area of science is being explored across the industry. At AbbVie, what was a small group of scientists working around them has since expanded to a robust, strategic team that spans discovery, development sciences, clinical and corporate strategy, with core members across therapeutic and functional areas.

This second wave of innovation is around how to selectively degrade proteins in certain tissues or organs, like proteins in immune cells only, Vasudevan says. Additionally, AbbVie is researching how to impact hard-to-treat disease areas, like neuroscience.

“The application of protein degradation to targets in neuroscience we care about requires degradomers to get into the brain,” Vasudevan says. “We’re focused on technologies and collaborations that allow us to better deliver to the brain.”