Undruggable cancer protein becomes druggable

Researchers discovered a cost-effective and efficient way to synthesize a rare compound found in a shrub

June 29, 2021
The Scitech

Curcusone D, the first synthesized BRAT-1 inhibitor, originally comes from the root of Jatropha curcas, a shrub native to the Americas. (Forest and Kim Starr)

Inspired by a rare compound found in a shrub native to North America, Mingji Dai, 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 lab. The compound - curcusone D - has the potential to help combat a protein found in many cancers, including some forms of breast, brain, colorectal, prostate, lung and liver cancers, among others. The protein, dubbed BRAT1, had previously been deemed “undruggable” 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 BRAT1 inhibitor.

Curcusones are compounds that come from a shrub named Jatropha curcas, also called the purging nut. Native to the Americas, it has spread to other continents, including Africa and Asia. Dai was interested in this family of compounds — curcusone A, B, C and D. Researchers tested the compounds on breast cancer cells and found curcusone D to be extremely effective at shutting down cancer cells. The protein they were targeting, 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 cancer cells’ DNA and keep them from repairing it, they can stop cancer cells from growing. The research was recently published in the Journal of the American Chemical Society. “Our compound can not only kill these cancer cells, it can stop their migration,” Dai said. “If we can keep the cancer from metastasizing, the patient can live longer.”

Dai and his team believe that as effective as curcusone D is by itself, it may be even more potent as part of a combination therapy. They tested it alongside 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. The next step will be to test the compound to ensure that it is not toxic to humans, something the researchers are optimistic about since the shrub it came from has been used as a traditional medicine in a number of cultures. Already, researchers from other entities have reached out to test the compound on the cancers they study, bringing hope for renewed therapeutics for treating the disease.

Source: Purdue University news release