Clues from nature inspire new anti-cancer drugs

St. Jude researchers have designed an efficient route to synthesizing a new type of anti-cancer drug, based on a chemical that bacteria use as a weapon against organisms they infect. The initial versions of the new drugs show significant activity against a range of cancer cells. Researchers believe that further refinements of the molecular structures could lead to a class of drugs that battle cancer in a way distinct from current drugs.

Thomas Webb, PhD, Chemical Biology and Therapeutics, and his colleagues published their findings on the new class of potential drugs, dubbed Judeamycins, in the advance online publication of the Journal of Medicinal Chemistry.

In their research, the investigators explored the structure of a class of natural products that work in a similar way in cancer cells called FR901464 and pladienolide A-G, which other scientists had isolated from bacteria. Researchers had found that some pladienolides were potent inhibitors of cancer cells, and one pladienolide derivative has already begun clinical testing against lung cancer. Scientists had also pinpointed how pladienolides kill cancer cells—by jamming a particular enzyme in the cancer cell’s machinery, called a spliceosome, which enables the cell to edit its genetic blueprint molecule, RNA, in the replication process. Without such editing, the cancer cells cannot proliferate, and they ultimately die off.

“We hypothesized that we could start with this natural structure and develop much more simplified molecules that we could more readily synthesize as spliceosome inhibitors,” said Webb, the paper’s senior author. “This simplified synthesis would enable us to selectively change any atom in the molecule. We could identify the features of these simplified molecules that are critical to activity and come up with new compounds that are much more active against cancers than the natural products that were the starting points.”

The researchers began with a 3-D model they developed that represented the key molecular features of two quite distinct spliceosome-inhibiting pladienolides and FR901464. From this model, the investigators designed and synthesized three new compounds, Judeamycin A, B and C. The scientists believed these compounds could serve as starting points for developing new anti-cancer drugs.

Importantly, the researchers simplified the molecular structures of the compounds to make them easier to synthesize in the laboratory. These simplified designs involved reducing the number of stereocenters in the structures of the molecules. Stereocenters are arrangements of atoms that could flip-flop during synthesis between mirror-image configurations. Synthetic chemists have long been challenged by stereocenters because only one configuration may yield an active drug, while molecules containing the mirror-image version can be inactive, and perhaps even harmful, contaminants. In their design, the researchers reduced the number of stereocenters from nine in the natural compounds down to three in their simplified versions.

The St. Jude team also designed the molecules such that they could be assembled from inexpensive chemicals. For example, one component of the drug molecules is derived from a commercially available insect repellent, indalon.

“By simplifying the synthesis and using components that are cheap and readily available, we can foresee making kilogram-quantities of these compounds for study and clinical trials,” Webb said.

Once the three compounds were synthesized, the researchers then tested how well the three compounds inhibited a range of cancer cells, including lung, colorectal, breast, prostate, ovarian and lymph node cancers. They found that one of the three compounds showed significant cancer-killing ability against the cancers.

“These compounds demonstrate that it is possible to identify the common molecular features of structurally diverse compounds that function via the same mechanism,” Webb said. “We can use those features to come up with a new structure that maintains much of the activity of the natural compounds, yet is a much simplified synthesis target. And importantly, we can easily tune the properties of these compounds so that they are better drugs, making them more selective and potent, and adjusting them to target different tumor types.”

The simplified drugs the investigators synthesized represent powerful research tools that other scientists could use to explore the basic mechanism of spliceosome inhibition. These insights, Webb said, could lead to new approaches to jamming the spliceosome to kill cancer cells.

Other St. Jude authors of this paper include Chandraiah Lagisetti and Tinopiwa Goronga, both of Chemical Biology and Therapeutics; Alan Pourpak, PhD, Qin Jiang and Xiaoli Cui, all of Pathology; and Stephan Morris, PhD, of Pathology and Oncology.

This research was supported in part by a National Cancer Institute Cancer Center Core grant and ALSAC.

October 2008