A breakthrough discovery in apoptosis

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Our teams advance leading-edge science through dynamic and collaborative approaches. Andrew Petros, principal research scientist at AbbVie, was part of a team that led the way to a breakthrough discovery in apoptosis.

In the early 1990s, a group of scientists from Abbott Laboratories, now AbbVie, began to pursue the potential of apoptosis as a therapeutic pathway in oncology. "Apoptosis was a potential mechanism for killing cancer cells that no one had really thought too much about," says Petros. "This was something completely different."

Determination

AbbVie scientists used high-powered imaging systems to create a structural map of the BCL-XL protein.

Researchers first focused on BCL-XL. According to Petros, the structure has a novel fold and generated a lot of excitement because, at the time, it wasn't clear which of the BCL proteins would be a good oncology target.

Once potential targets were identified, the team worked to discover a small molecule that could bind to these BCL proteins and induce cancer cell death.

Led by Steve Fesik, then head of oncology discovery at Abbott and now at the Vanderbilt University Medical Center, the process of finding the right molecule was slow and methodical.

After five years, the team identified a molecule that could bind to the active groove on the surface of the BCL-XL protein. The molecule proved potent at activating cell death, but its lack of oral bioavailability made it a poor choice as a therapy for patients who, as a group, generally prefer pills.

"There were times we thought we wouldn't be able to do it, but Steve was determined not to let this fail. And each step of the way we'd get just enough good data to convince people we should keep working at it," says Petros.

Collaboration

It would take another two years of formulation work and extensive cross-disciplinary collaboration to move the project forward. More issues emerged in the clinic, and the team shifted its focus to apoptotic proteins it hadn't previously considered.

"Based on extensive biological studies, we realized BCL-XL was the problem and we shifted our focus to another protein in the family," says Petros. "But we didn't have to start over; we had structural insight."

By building on years of research and insight, the team has continued to advance the science of the BCL family of proteins, including coming back to BCL-XL. In early 2015, Science Translational Medicine published a paper detailing the foundational biology work being done by AbbVie scientists on the BCL-XL protein and its role in solid tumors.

Andrew Petros, Principal Research Scientist

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