Slow and steady improvements to a well-known cancer drug ultimately resulted in the discovery of a new way to modify and a less expensive way to produce one of oncology’s classic first-line therapies and most successful chemotherapeutics. By working to understand the interaction between the drug vinblastine and its protein target tubulin, researchers at The Scripps Research Institute uncovered something they think will impact treatment for a wide variety of cancers.

The team didn’t just develop a second-generation vinblastine. They developed a new approach to modify the molecule. “There is a great role for chemistry in drug discovery in non-traditional areas,” says Dale Boger, chair of the Department of Chemistry at The Scripps Research Institute and in whose lab the work was done. Drugmaker Bristol-Myers Squibb is already collaborating with the group.

Many in the drug development community long thought synthesizing a better vinblastine that was less prone to generating resistance wasn’t possible. The new molecule is not any simpler. But Boger says he and his colleagues developed sophisticated chemistry to attack the problem. The team figured out how to synthesize the new form of the drug—starting with a commercially available natural product source in just three steps—using elemental iron. While the innovation was published late last year, the current work has clinical relevance. The new vinblastine analogue is more potent, has greater activity against resistance, and could be made inexpensively. “It might actually be less expensive” says Boger. This is because vinblastine is purified from the cultivated periwinkle plant and is present in only trace amounts, less than 0.0001 percent of the dry leaf weight. Huge yields are necessary to prepare the clinical material used to treat testicular, ovarian, breast, bladder, lung cancers and lymphoma.

When Boger’s lab started working on the drug seven to eight years ago, they wanted to understand how the compound interacts with its biological target. The drug and other agents that target tubulin and microtubules work by preventing microtubules, the cell’s structural scaffold, from duplicating and separating properly during cell division. This puts the cells in a state of suspended division with cell death the final outcome. Because cancer cells multiply and divide faster than normal cells, they are more susceptible to these drugs.

The problem is that cells have a protein pump that spits out the drug, and resistance to anti-microtubule agents develops when cancer cells with greater amounts of this pump are left behind following treatment. They eventually multiply, and the cancer reforms with cells that are no longer responsive to this class of drug because it can’t accumulate in high enough concentrations inside the cell.

The Scripps Research Institute team found several analogues based on their new chemistry that were as effective at killing resistant cells as the original vinblastine was at killing non-resistant cancer cells. They recruited their existing collaborator, Bristol-Myers Squibb, to see if it was interested in repeating the experiments to test the accuracy of the results and expand the work into 15 cancer cell lines. The company could, so a clinical trial might not be far away. The current results are published in the journal Medicinal Chemistry Letters. Since other microtubule-disrupting chemotherapeutics could be modified by this new chemistry, the work has potential to bring unexpected innovation to an old class of drugs.