Thanks to the bush, ‘incurable’ cancer protein becomes drugable

A chemist from Purdue University has found a way to synthesize a compound to combat a previously “incurable” cancer protein with benefits for a wide range of cancers.

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 discovered 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 breast, brain, colorectal, prostate, lung, and liver cancers, among others. The protein, called BRAT1, was previously considered “incurable” because of 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 that come from a shrub called Jatropha curcas, also known as the purification 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 cancer treatment – and is also a proposed inexpensive source of biodiesel.

Dai was interested in this family of compounds – curcuson 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 showed quite potent anti-cancer activity and may lead to new mechanisms to fight cancer.”

Researchers tested the compounds on breast cancer cells and found that curcusone D is extremely effective at knocking out cancer cells. The protein they targeted, BRAT1, regulates the response to DNA damage and DNA repair in cancer cells. Cancer cells grow very quickly and make a lot of DNA. If scientists can damage the DNA of cancer cells and prevent them from repairing it, they can stop the growth of cancer cells.

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

Preventing cancer from spreading through the body – metastasizing – is key to keeping a cancer patient alive. Once cancer begins to migrate from its native organ to different 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 that,” Dai said. “But as far as it inhibits BRAT1 protein, there are no other compounds that can do that.”

Dai and his team believe that curcusone D, just as effective as on its own, can be even more potent as part of a combination therapy. They tested it alongside a DNA damaging agent already 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 while the shrub they come from is common and inexpensive, it takes massive amounts of the shrub to provide even a small amount of the compounds. Even then, it is difficult to separate the compounds they were interested in from the rest of the chemicals in the roots of the shrub.

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

That small yield is relevant to production, because if it is effective as a cancer treatment, pharmacists will need much more of it. In addition, having an abundant supply of the compounds makes studying them easier, faster and cheaper.

“That’s why a new synthesis is so important,” said Dai. “We can use the synthesis to produce more compounds in a purer form for biological research, thus improving the field. From there we can make analogues of the compound to improve 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 given that the shrub it comes from is used as a traditional medicine in a number of cultures. Researchers from other entities have already reached out to test the compound in the cancers they are studying, raising hope for renewed therapies to treat the disease.

“Many of our most successful cancer drugs come from nature,” said Dai. “Much of the low-hanging fruit, the compounds that are easy to isolate or synthesize, have already been sieved and picked. We’re looking for things that haven’t been thought of before. Once we have the chemistry, we can find the molecules we’re interested in. and study their biological function. ”