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Structural Biology Helps Drug Discovery Print

Last year, drug discovery company Plexxikon made front-page news with its highly successful anti-cancer drug, Zelboraf, a product that was chemically optimized using data from ALS x-rays. Designed to disrupt malignant melanoma, the drug was so successful (see before and after scans of a patient below) in human testing that trials were halted so that patients in the trial could all be given Zelboraf. Zelboraf marked a significant advancement for patients with metastatic melanoma who historically have had very limited treatment options.

Plexxikon did the majority of the molecular imaging needed to develop Zelboraf at the ALS, where they’ve contracted beamtime for the past ten years. The company also collected some of their data at SLAC and Argonne National Laboratory, but the bulk of the protein crystallography work was conducted at the ALS Beamline 8.3.1, a macromolecular crystallography facility.

Plexxikon started out by doing what most users do at the ALS’ eight protein crystallography beamlimes—solving protein structures and co-structures of protein targets and potential drug candidates. Once they had a high-resolution image of mutant BRAF, a protein that drives half of all melanomas, Plexxikon moved on to obtain countless more, binding each to a different drug-like molecule and viewing atom-by-atom how the drugs bound to BRAF. This image-heavy approach, termed Scaffold-Based Drug Discovery™, was pioneered by Plexxikon. The co-structure information was key to optimization of the eventual lead drug candidate, Zelboraf (PLX4032), which was most effective in “turning off” the mutated BRAF protein in melanoma patients.

zelboraf structure

james holton“I think it’s an excellent example of how structural biology helps drug discovery,” says 8.3.1 Beamline Scientist James Holton (at left). “It’s nice for me as a structural biologist to see companies like Plexxikon being so successful.”

Zelboraf made headlines, but Plexxikon also conducts other important drug development research at the ALS.  The company is currently testing other drug candidates that are the result of their x-ray co-crystallography research. As members of the beamline 8.3.1 PRT, Plexxikon gets regular, guaranteed beam time. The company also pays proprietary research fees for each shift they use at the ALS.

“The ALS is Plexxikon’s premier data collection facility,” says Holton. “I think they like being associated with a center of innovation and they also really like the level of user support that they get here.”

Though Holton doesn’t get involved in Plexxikon’s research directly due to intellectual property protections, he is a major resource to their crystallographers when they come to use the beamline. Plexxikon values the expertise of the user support they receive and the reliability of the facilities at the ALS, says Kathy Glaub, President of Business Development at Plexxikon.



Before and after scans of a patient treated with Zelboraf. (Courtesy of the Peter MacCallum Cancer Centre)