Mapping the Target Landscape
In the early 1990s a group of scientists wanted to better understand apoptosis. They wondered if this cellular ability to self-destruct could lead to a cancer-fighting medicine. Several proteins help in the apoptotic process, some that cause cell death and some that prevent it. But they had no idea what those proteins looked like, so there was no way to harness them for drug development.
Researchers took BCL-XL, the easiest-to-access protein, and created a picture of it using two high-powered imaging systems – nuclear magnetic resonance spectroscopy and X-ray crystallography.
According to Andrew Petros, Ph.D., senior principal research scientist, AbbVie, who worked on the project later on, the structure “was 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.”
Now they could try to find small molecules that could bind to, and inhibit these BCL proteins on the surface of cancer cells. The objective was to reset the cell-death program within the cancer cells and induce them to commit suicide.
Just Enough to Keep Going
Led by Steve Fesik, who is now at the Vanderbilt University Medical Center, the process of finding the right molecule was slow and methodical. After five years, they identified a molecule that could bind to the “active” groove on the surface of the BCL-XL protein. “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,” Petros says.
The molecule proved potent at killing cancer cells by activating cell death, but had no oral bioavailability; it couldn’t be made into a pill because the body wouldn’t be able to absorb it. It would have to be injected, but cancer patients and oncologists have historically been more receptive to pills than injections.
A Eureka Moment
It would take another two years for scientists to formulate the molecule as a pill, and in 2005 clinical trials started.
The bad news came shortly thereafter. The molecule killed cancer cells, but also blood platelets – an essential part of the body’s systems that initiate blood clotting at the site of a wound or injury. This finding led scientists to decide not to move on with a drug that limited patient use or required hospitalization during treatment.
Back to the drawing board, they realized that there were several other apoptotic proteins they hadn’t previously considered. And by changing one amino acid in the structure of the BCL-XL molecule they turned it into a BCL-2 selective compound. “Based on extensive biological studies, we realized BCL-XL was the problem,” Petros says. “But we thought, if we can make a more selective molecule that binds only to BCL-2, we may be on the right track. We didn’t have to start over; we had structural insight.”
More Promise Ahead
It would take four more years to advance a new molecule through the clinic and ultimately make it available to patients, and investigational trials continue for treating different blood cancers.
And research continues on BCL-XL. Early in 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.