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September 13, 2004
Scientists construct 3D model of anti-cancer molecule
by eric rangus & Beverly Clark
Emory scientists, 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 could potentially lead to the creation of more effective cancer treatments.
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 the drug epothilone A interacts with a key protein that controls cell division. The final three-dimensional image is the result of more than two years of trial-and-error mapping by the researchers.
“We want to analyze the atomic-level difference of these drugs,” said Jim Nettles, lead author of the paper and a doctoral candidate in molecular and systems pharmacology. Finalizing the model required the researchers to sample tens of thousands of other models before they discovered an accurate one. “If we develop the three-dimensional model of the structure, we can make changes to the molecules in response to changes in molecular biology,” Nettles said.
The researchers have now examined two drug families—epothilones and taxanes. The latter includes the anticancer drug Taxol, already in use. Their paper outlining the Taxol model was published in 2001. The work on these anti-cancer drugs builds on other research including that of Winship Cancer Institute researcher Evi Giannakakou, who Nettles said had built what was previously the best model of epothilone.
Both epothilones and taxanes work to halt the division of cancer cells by binding to the same site on a protein called tubulin, which 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.
“Were you to compromise the function of microtubules, you would prevent the cell from dividing,” said Jim Snyder, Emory’s director of biostructural research and a paper co-author. Since cancer cells are notable for their rapid division, stopping them from dividing is crucial.
To do so, epothilones stabilize the reproducing cell’s dynamic microtubules, preventing it from dividing and eventually leading to cell death. Taxol works in the same way, but it carries side effects, such as acquired resistance, which led researchers to investigate the next generation—epothilones. Three other similar molecules also exist, and all five are found in nature. Epothilones, for example, are found in soil bacteria.
“But they all have very different three-dimensional structures,” Snyder said. “Yet it’s known that all five of these molecules work by stabilizing microtubules and causing cancer cells to die in almost the same way. They all bind to the same place.”
But exactly how they bind has been the unknown. The map of Taxol was made in 2001, more than a decade after it hit the market. “Epothilone is the next generation of agents that bind to this particular site,” Snyder said. “So our goal is to understand the three-dimensional structure of the complex between each of these five molecules and the protein, and then use that information to design better drugs in the same class.”
Therefore, once the binding structure has been mapped, it can be re-created synthetically, and better drugs using the properties of the molecule can be formed.
The researchers now have moved on to the third molecule, discodermolide, and they are halfway to mapping its three-dimensional structure. Discodermolide has not yet reached the clinical stage yet, therefore this research could be far ahead of the curve.
“Hopefully we’ll be able to map this one faster since we’ve learned how,” said Snyder, referencing the two-year effort that led to the epothilone map.
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