|Scientists at Emory University, in collaboration with researchers at three national laboratories, have solved the structural puzzle of how an emerging class of promising cancer drugs work to halt cell division. The discovery potentially opens the door to the creation of more effective cancer treatments.
"Uncovering and mapping the structure of this model system will assist scientists around the world in creating new compounds that hopefully will lead to new cancer drugs," says researcher Jim Snyder, an Emory chemist and director of biostructural research at the university.
The results, reported in the Aug. 6 issue of the journal Science, include the first three-dimensional, atomic-scale images of the binding site where one of the drugs, epothilone A, interacts with a key protein controlling cell division. The researchers have now examined two drug families - the epothilones and taxanes, which include the anti-cancer drug Taxol already in use. Both drugs work to halt the division of cancer cells by binding to the same site on a protein called tubulin that is involved in cell division. Tubulin is the major component of microtubules, the hollow cylinders that serve as a skeletal system for cells and a scaffold for chromosomes in the dividing cell. When epothilones or taxanes bind to tubulin, the protein loses its flexibility and the microtubules can no longer disassemble, halting cell division.
To build the model, the Emory team used diffraction data gathered from an electron microscope at Lawrence Berkeley National Laboratory. The data allowed them to "see" the differences in the atomic positions associated with the two drugs that explained their activities within a cell. The work involved using computers to test thousands of possible solutions against the diffractions along with extensive biological data regarding drug activity.
Jim Nettles, an Emory doctoral candidate in molecular and systems pharmacology who is first author of the paper, says the research "was a highly collaborative project that crossed formal disciplines and brought together researchers with strong backgrounds in chemistry, biology, physics and pharmacology, which was essential for putting the pieces of this puzzle together." He says that in addition to this basic research, it is hoped that the model system also will become useful as a clinical tool for pharmacogenetic profiling - matching the best drug for a given patient.
Other collaborators included researchers at the U.S. Department of Energy's Brookhaven National Laboratory and the structural biology laboratory at the National Institute of Environmental Health Sciences.