SLAC beam used to develop new melanoma drug

A melanoma drug approved last week by the U.S. Food and Drug Administration was developed with the help of an X-ray light source at the SLAC National Accelerator Laboratory, as well as two other federally funded national labs.

The drug, Zelboraf, for late-stage melanoma in patients whose cancer has a certain genetic mutation, was approved Aug. 17 under an expedited process for drugs that may offer major advances or provide treatment where no adequate therapy exists.

Researchers used SLAC’s X-ray light equipment, the Stanford Synchrotron Radiation Lightsource (SSRL), to see the structure of the disease-causing enzyme at its most basic, three-dimensional level, enabling them to design a corresponding molecule that inhibits it.

“The X-ray becomes a very useful technology because the (cancer) protein is so small you can’t detect it with the eye or even with the most powerful microscope,” said Chao Zhang, a structural biologist with the Berkeley-based drug discovery company Plexxikon Inc.

“Basically, the small molecule we design is a perfect geometric complement, fitting the shape of the active site so the (cancer) protein is stopped from performing its function. That’s why we need the 3-dimensional structure,” Zhang said.

Zhang was one of the lead scientists working on Zelboraf, then called PLX4032 by researchers, at SLAC in 2005. Work also was done at Lawrence Berkeley National Laboratory and Argonne National Laboratory near Chicago.

In a technique known as macromolecular X-ray crystallography, images from the X-ray light source are used to create 3-dimensional structures of the cancer protein in a multi-phase process of refinement to get the optimal fit.

“We typically go through hundreds of small molecules in the process,” Zhang said. In the case of Zelboraf, it took about five rounds, with 20 to 50 molecules in each attempt.

“Because all the facilities are busy, we use whatever time we can get,” Zhou said. “The time is precious because a lot of labs from academic institutions and industry share the same facilities.”

SLAC said about 1,500 scientists use the SSRL light source every year, running experiments in life sciences, materials science, geology and chemistry. Access is offered through a peer-review process at no charge for scientists conducting non-proprietary research. Access is available for proprietary research on a “cost-recovery” basis.

“When it’s in user mode (and not down for maintenance), it’s used 24 hours a day,” said Axel Brunger, a professor of molecular and cellular physiology, and of neurology and neurological sciences at Stanford.

Brunger uses the SSRL light source for his own work and has served on the scientific advisory board of Plexxikon, a 10-year-old company that was acquired in April by the Japanese pharmaceutical company Daiichi Sankyo, Co., Ltd.

“People get assigned certain shifts — it can be day or night. If it’s a night shift, you just have to be prepared to spend the night there.”

But researchers don’t necessarily have to be physically present to run the experiments.

“They can run it remotely from their computers, so the only thing they have to do is ship the crystals to the facility by Fedex and the (SLAC) staff will actually mount the robots,” Brunger said.

“This (light source) technology is a wonderful example of how innovations at our national laboratories lead to discoveries in a wide variety of fields,” said U.S. Secretary of Energy Steven Chu in a prepared statement. Chu, a former Stanford physics professor and 1997 physics Nobel Prize winner, was director of Lawrence Berkeley from 2004 to 2009.

The Department of Energy supports five advanced, X-ray light sources, football-field-sized installations that produce precise, high-intensity X-ray beams.