“Undruggable” cancer protein targeted by compound from shrub root

Scientists at Purdue University and the Scripps Research Institute have identified a natural compound from a common shrub that could help fight cancer. The compound is the first found to inhibit a cancer protein that was previously considered “undruggable.”

Cancer is notoriously effective at growing out of control and eventually spreading to other locations in the body. To manage this feat, cancer cells can repair damage to their DNA more readily than regular cells.

In some types of cancer, such as brain, breast, colorectal, prostate, lung and liver cancers, a protein called BRAT1 regulates that DNA damage response and repair. Normally that would make it a good candidate for therapeutic targeting, but unfortunately BRAT1 has long been thought to be undruggable.

However, in the new study researchers finally identified a compound that can inhibit BRAT1. That works to damage the DNA of cancer cells and prevents them from repairing it.

“For killing cancer cells and stopping migration, there are other compounds that do that,” says Mingji Dai, lead author of the study. “But as far as inhibiting the BRAT1 protein, there are no other compounds that can do that.”

The key to the new study was a shrub called Jatropha curcas, which is common in and native to the Americas. The plant is showing promise as a source of biofuel, but also of interest are the potentially medicinal compounds it contains. In this case, the researchers focused on a family of compounds called curcusones.

“We were very interested by these compounds’ novel structure,” says Dai. “We were intrigued by their biological function; they showed quite potent anti-cancer activity and may lead to new mechanisms to combat cancer.”

The team tested four of these compounds – curcusone A, B, C and D – against breast cancer cells in culture. They found that curcusone D was the most promising, shutting down tumors very effectively. It worked even better when paired with an existing drug, called etoposide, which damages the cancer’s DNA and has already been approved by the FDA.

One hurdle is that the yield of curcusone D from the roots of the shrub is quite small, so it isn’t practical to harvest for useful amounts. But the team has developed a method for synthesizing it in the lab, which they say can help them create more of the compound, and in a purer form.

As promising as the results have been so far, there’s still plenty more work to do. Next up, the team will investigate whether it is toxic to human cells, but given its history in traditional medicine, the researchers say it is likely to be safe.

The research was published in the Journal of the American Chemical Society.

Source: Purdue University

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