Rare ingredients found in the bush could help fight previously ‘irreplaceable’ cancer proteins

A chemist from Purdue University has found a way to synthesize compounds to fight the previously “restless” cancer protein with advantages in countless types of cancer.

Inspired by a rare compound found in shrubs native to North America, Mingji Dai, a chemistry professor and scientist at Purdue University’s Cancer Research Center, studied the compound and discovered a cost-effective and efficient way to synthesize it in a laboratory. The compound – curcusone D – has the potential to help fight proteins found in many cancers, including some forms of cancer of the breast, brain, colon, prostate, lung and liver, among others. The protein, called BRAT1, was previously considered “restless” due to its chemical properties. In collaboration with a group of Alexander Adibekian of the Scripps Research Institute, they linked curcun D to BRAT1 and confirmed curcun D as the first BRAT1 inhibitor.

Curcusons are compounds derived from a shrub called Jatropha curcas, also called a nut. Originally from America, it spread to other continents, including Africa and Asia. The plant has long been used for its medicinal properties – including cancer treatment – as well as a proposed cheap source of biodiesel.

Daia was interested in this family of compounds – curcun A, B, C and D.

“We were very interested in the new structure of these compounds,” Dai said. “We were intrigued by their biological function; they showed quite powerful anticancer activity and could lead to new mechanisms to fight cancer.”

The researchers tested the compounds on breast cancer cells and found that curcusone D was extremely effective in killing cancer cells. The targeting protein, BRAT1, regulates the response to DNA damage and DNA repair in cancer cells. Cancer cells grow very fast and produce a lot of DNA. If scientists can damage the DNA of cancer cells and prevent them from repairing it, they can stop cell growth.

“Our union can not only kill these cancer cells, but it can stop their migration,” Dai said. “If we can prevent the cancer from metastasizing, the patient can live longer.”

Stopping the spread of cancer throughout the body – metastasis – is key to saving the life of a cancer patient. Once the cancer begins to migrate from its original organ to various bodily systems, new symptoms begin to develop, often threatening the patient’s life.

“There are other compounds that kill cancer cells and stop migration,” Dai said. “But when it comes to inhibiting the BRAT1 protein, there are no other compounds that can do that.”

Dai and his team believe that as effective as curcusone D itself is, it may be even more powerful as part of combination therapy. They tested it along with a DNA-damaging agent already approved by the Food and Drug Administration and found that this combination therapy was much more effective.

One difficulty in studying curcusone as a potential cancer treatment is that, although the shrub they come from is common and inexpensive, huge amounts of shrub are needed to obtain even a small amount of the compound. Even then, it is difficult to separate the compounds that interested them from the rest of the chemicals in the bush roots.

“In nature, the plant does not produce much of this compound,” Dai said. “It might take you about 100 pounds of dried plant roots to get about a quarter of a teaspoon of that substance – a yield of 0.002%.”

This small yield is relevant to production because if it is effective as a cancer treatment, pharmacists will need a lot more. In addition, the abundant supply of compounds makes their study easier, faster and cheaper.

“That’s why the new synthesis is so important,” Dai said. “We can use the synthesis to produce more compounds in purer form for biological studies, which allows us to advance the field. From there, we can make analogs of the compound to improve its strength and reduce its potential for side effects.”

The next step will be to test the compound to ensure it is not toxic to humans, in which researchers are optimistic since the shrub from which it originated is used as a traditional remedy in many cultures. Researchers from other entities have already reached out to test the compounds for the cancers they are studying, bringing hope for new therapies to treat the disease.

“Many of our most successful cancer drugs come from nature,” Dai said. “A lot of low-hanging fruits, compounds that are easy to isolate or synthesize, have already been tested and picked up. We look for things no one has thought of before. Once we have chemistry, we can build molecules that interest us and study their biological function.”

This research was funded through grants from the National Institutes of Health and the National Science Foundation. U.S. Patent Application No. 63 / 084,594 covers this finding.

Source:

Journal reference:

Cui, C., and others. (2021) Overall synthesis and target identification of curcusone diterpene. Journal of the American Chemical Society. doi.org/10.1021/jacs.1c00557.

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