‘Unusable’ cancer protein becomes intoxicating, thanks to shrub

A Purdue University chemist has found a way to synthesize a compound to fight a previously ‘unbreakable’ cancer protein, with benefits in a multitude of cancers.

Inspired by a rare shrub found in a shrub in North America, Mingji Dai, a professor of chemistry and a scientist at the Purdue University Center for Cancer Research, studied the compound and discovered a cost-effective and efficient way. to synthesize it in the laboratory. . The compound – curcusone D – can help fight proteins found in many cancers, including some forms of breast, brain, colorectal, prostate, lung and liver cancers. The protein, called BRAT1, was previously considered an insoluble agent due to 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 BRAT1 inhibitor.

Curcusones are compounds derived from a shrub called Jatropha curcas, also called the coil nut. Native to the Americas, it has spread to other continents, including Africa and Asia. The plant has long been used for medicinal properties – including the treatment of cancer – as well as 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,” Dai said. “We were intrigued by their biological function; they showed a very powerful anti-cancer activity and could lead to new mechanisms to fight cancer.”

Researchers have tested the compounds on breast cancer cells and found that curcusone D is extremely effective in shutting down cancer cells. The protein they target, BRAT1, regulates DNA damage response and DNA repair in cancer cells. Cancer cells grow very fast and make a lot of DNA. If scientists can damage and prevent cancer cells’ DNA from repairing it, they can stop cancer cells from growing.

“Our compound can not only kill these cancer cells, it can also stop their migration,” Dai said. “If we metastasize to cancer, the patient can live longer.”

Preventing cancer from spreading through the body – metastasizing – is key to preserving the life of a cancer patient. Once cancer begins to migrate from the original organ into various body 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 it,” Dai said. “But as far as it inhibits the BRAT1 protein, there are no other compounds that can do that.”

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

One problem with studying curcusones as possible cancer treatments, is that although the shrub from which they come is common and inexpensive, it requires large amounts of shrub to yield even a small amount of the compounds. Even then, it is difficult to separate the compounds in which they are interested from the rest of the chemicals in the shrub roots.

“In nature, the plant does not produce much of this compound,” Dai said. “You may need as much as 100 pounds of the plant’s dry roots to get about a quarter teaspoon of the substance – a yield of 0.002%.”

That small yield is relevant to production, because if it is effective as a cancer treatment, pharmacists will need much more of it. Moreover, studying it makes an abundance of stock connections easier, faster and cheaper.

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

The next step will be to test the compound to make sure it is not toxic to humans, something the researchers are optimistic about, as the shrub from which it comes has been used as a traditional medicine in a number of cultures. Researchers from other institutions have already tried to test the compound on the cancer they are studying, and give hope for renewed medicine for the treatment of the disease.

“Many of our most successful cancer drugs come from nature,” Dai said. “Many fruits that hang low, the compounds that are easily isolated or synthesizable, have already been selected and selected. We are looking for things that no one has thought of before. Once we have the chemistry, we can find the molecules we are interested in and study their biological function. ‘