A Purdue University chemist has found a way to synthesize a compound to fight a previously “indruggable” cancer protein with benefits across a myriad of cancer types.
Inspired by a rare compound found in a shrub native to North America, Mingji Dai, a chemistry professor and scientist at the Purdue University Center for Cancer Research, studied the compound and found a cost-effective and efficient way to synthesize it in the lab. . The compound – curcusone D – has the potential to help fight a protein found in many cancers, including some forms of breast, brain, colorectal, prostate, lung, and liver cancer, among others. The protein, dubbed BRAT1, had previously been deemed “indruggable” for its chemical properties. In collaboration with Alexander Adibekian’s group at the Scripps Research Institute, they linked curcusone D to BRAT1 and validated curcusone D as the first inhibitor of BRAT1.
Curcusones are compounds that come from a shrub called Jatropha curcas, also known as purge nuts. Originally from the Americas, it has spread to other continents, especially Africa and Asia. The plant has long been used for its medicinal properties – including cancer treatment – in addition to being a proposed inexpensive source of biodiesel.
Dai was interested in this family of compounds – curcusone A, B, C and D.
“We were very interested in the new structure of these compounds,” said Dai. “We were intrigued by their biological function; they have shown quite potent anticancer activity and may 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 stopping cancer cells. The protein they were targeting, BRAT1, regulates the response to DNA damage and DNA repair in cancer cells. Cancer cells grow very quickly and produce a lot of DNA. If scientists can damage the DNA of cancer cells and prevent them from repairing it, they can prevent cancer cells from growing.
“Our compound can not only kill these cancer cells, but also stop their migration,” Dai said. “If we can stop the cancer from metastasizing, the patient can live longer.”
Preventing cancer from spreading throughout the body – metastasizing – is essential to preserving the life of a cancer patient. Once cancer begins to migrate from its original organ to different bodily systems, new symptoms begin to develop, often threatening the patient’s life.
“To kill cancer cells and stop migration, there are other compounds that do this,” Dai said. “But when it comes to inhibiting the BRAT1 protein, no other compound can do it.”
Dai and her team believe that, as effective as curcusone D on its own, it can be even more potent in combination therapy. They tested it with a DNA damaging agent that has already been approved by the Food and Drug Administration and found that this combination therapy is much more effective.
One difficulty in studying curcusones as potential cancer treatments is that although the shrub they come from is common and inexpensive, it takes massive amounts of the shrub to produce even a small amount of the compounds. Even then, it is difficult to separate the compounds that interested them from the rest of the chemicals present in the roots of the shrub.
“In nature, the plant doesn’t produce a lot of this compound,” Dai said. “You might need up to 100 pounds of the plant’s dry roots to get about a quarter of a teaspoon of the stuff – a 0.002% yield.”
This small yield is relevant for production, because if it is effective as a cancer treatment, pharmacists will need a lot more. In addition, having an abundant supply of compounds makes their study easier, faster and less expensive.
“This is why a new synthesis is so important,” Dai said. “We can use synthesis to produce more compounds in a purer form for biological study, which allows us to move the field forward. From there, we can make analogues of the compound to improve its potency and reduce the potential for side effects.
The next step will be to test the compound to make sure it is not toxic to humans, which the researchers are optimistic about since the shrub it comes from has been used as a traditional medicine in a number of cultures. Already, researchers from other entities have sought to test the compound on the cancers they are studying, raising hope for new therapies to treat the disease.
“Many of our most effective cancer drugs come from nature,” Dai said. “Much of the fruit at hand, the compounds that are easy to isolate or synthesize, have already been sifted and picked. We are looking for things that no one has thought of before. Once we have the chemistry, we can build the molecules that interest us and study their biological function. “
This research was funded by grants from the National Institutes of Health and the National Science Foundation. Patent application US 63/084 594 covers this discovery.