Drug mechanism discovery encourages designers
chemotherapy drugs will be encouraged by the latest discovery that
has isolated the independent mechanisms of action of two anticancer
drugs. This revelation provides drug designers with more
flexibility in synthesizing new and improved forms of the drugs.
The discovery is important because it reveals the drugs have more than one way in combating the spread of tumours and provides drug designers with alternatives when attempting to synthesize novel analogues of these drugs.
A team of scientists experimented on two anticancer drug families, the taxanes, which include Taxol and the epithilones. They found that while the two drugs bind to the same region of the protein, they do not bind to the same pharmacophore, a tubulin-binding site, because they bind in such different ways. This might help to explain the mutations that bind to tubulin producing strong resistance to one of these anticancer drugs provide only limited resistance to the other.
Kenneth Downing, the principal investigator for this study said: "Our ultimate goal is to identify all of the different mechanisms that nature uses to stabilize tubulin activity and block mitosis. Ideally, chemists will be able to use our data to develop improved anticancer drugs."
They made their determinations after producing the first-ever 3D, atomic-scale images of the binding site where one of the epothilones interacts with a tubulin, crucial to mitosis (cell division). Tubulin is the major constituent of microtubules, hollow cylinders that serve as a skeletal system for cells.
Downing added: "By binding to tubulin, epothilone acts as a microtubule stabilizer. Tubulin loses its flexibility and the microtubules can no longer disassemble. That means cell division stops."
Since cancer is the result of cell division run amok, it has long been recognized that microtubule stabilizers could prove valuable as cancer chemotherapy agents. Taxanes are also microtubule stabilizers that bind with tubulin and has been shown in clinical to be an effective treatment for a number of cancers including ovarian, breast, and lung. However, Taxol has a number of unpleasant side effects on patients, and treatment for recurrent cancers is often unsuccessful.
It is believed a tubulin-binding site called a pharmacophore, common to both families and with a specific set of chemical characteristics, could be found. This would be the route through which safer and more effective artificial forms of the taxanes, epothilones, and other natural anticancer compounds could be synthesized.
Through a combination of electron crystallography, nuclear magnetic resonance (NMR) spectroscopy, and molecular modelling, Downing and his collaborators were able to create a high-resolution, 3-D structural model of the site where the epothilone EpoA binds with tubulin.
Huilin Li, of the Brookhaven National Laboratory said: "Using electron crystallography, we obtained the high-resolution electron density map, and were clearly able to localize the drug inside the protein density."
Li said that because of the flexible nature of the drug structure, the exact binding structure for the drug was difficult to isolate. Computer modelling was used to come up with a drug structure that fit the observed density map.
Downing added: "Our ultimate goal is to identify all of the different mechanisms that nature uses to stabilize tubulin activity and block mitosis. Ideally, chemists will be able to use our data to develop improved anticancer drugs."
