A plant found only in the rainforests of Australia provides a revolutionary cure for cancer

In nature, this compound is found in the seeds of the pink fruit of the flowering tree Fontainea picrosperma. (CREDIT: Creative Commons)

Researchers at Stanford University have discovered a fast and sustainable way to synthetically produce a promising cancer-fighting compound right in the lab. The availability of this compound has been limited because its only currently known natural source is a single plant species found exclusively in a small area of ​​rainforest in northeastern Australia.

The compound, designated EBC-46 and technically called tigilanol tiglat, works by stimulating a local immune response against tumors. The reaction destroys the tumor’s blood vessels and ultimately kills its cancer cells. EBC-46 has recently entered human clinical trials after its extremely high efficacy in treating cancer in dogs.

However, given its complex structure, EBC-46 proved to be synthetically inaccessible, meaning that there was no plausible way to produce it practically in a laboratory. However, thanks to a clever process, Stanford researchers have demonstrated for the first time how to chemically convert abundant plant-based source material into EBC-46.

As a bonus, this process can produce EBC-46 “analogues” – compounds that are chemically similar but could be even more effective and potentially treat a surprisingly wide range of other serious diseases. These diseases, including AIDS, multiple sclerosis, and Alzheimer’s disease, share common biological pathways that are targeted by EBC-46, a key enzyme called protein kinase C, or PKC.

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“We are very excited to announce the first scalable synthesis of EBC-46,” said Paul Wender, Francis W. Bergstrom Professor in the School of Humanities and Sciences, Professor of Chemistry and, by kind permission, Chemical and Systems Biology at Stanford. and corresponding author of a study describing the results in the journal Nature Chemistry. “Being able to get EBC-46 in the lab really opens up huge opportunities for research and clinical research.”

The co-authors of the study are Zachary Gentry, David Fanelli, Owen McAteer, and Edward Nju, all of whom are graduate students in Vender’s lab, along with former member Quang Luu-Nguyen.

Wender expressed great satisfaction with the research team’s breakthrough in the synthesis of EBC-46. “If you visited the lab in the first few weeks after they succeeded,” Wender said, “you would see my star colleagues smiling from ear to ear. They were able to do what many people thought was impossible.”

Graduate students Edward Nju, David Fanelli, Zach Gentry, and Owen McAteer. These researchers achieved the synthesis of the anti-cancer compound EBC-46. (CREDIT: Paul Wender)

From a remote region

Tigilanol tiglat was originally discovered by the Australian company QBiotics during an automated selection process for drug candidates. In nature, this compound is found in the seeds of the pink fruit of the flowering tree Fontainea picrosperma. Marsupials such as musky kangaroo rats that eat blush fruit avoid seeds rich in tigilanol tiglat, which cause vomiting and diarrhea when ingested.

Administration of much lower doses of EBC-46 directly to certain solid tumors alters cellular signaling by PKC. Specifically, EBC-46 is thought to activate certain forms of PKC, which in turn affect the activity of various proteins in cancer cells, inducing an immune response in the host.

Paul Wender, Francis W. Bergstrom Professor in the School of Humanities and Sciences, Professor of Chemistry. (CREDIT: Paul Wender)

The resulting inflammation makes the tumor vasculature or blood vessels leaky, and this hemorrhage leads to the death of the tumor growth. In the case of external, cutaneous malignancies, tumors slough off and fall off, and EBC-46 delivery routes to internal tumors are being studied.

In 2020, the European Medicines Agency and the US Food and Drug Administration approved an EBC-46 drug sold under the brand name Stelfonta for the treatment of mast cell cancer, the most common skin tumor in dogs.

The study showed a 75% cure after one injection and 88% after the second dose. Since then, clinical trials have begun for skin, head and neck, and soft tissue cancers in humans.

Based on these new studies and clinical needs, combined with the geographic limitations of the original seeds, the scientists considered establishing dedicated rouge plantations. But this raises many problems.

First, trees require pollination, which means that suitable pollinating animals must be on hand, plus the trees must be planted at the appropriate density and at the appropriate spacing to promote pollination. In addition, trees are affected by seasonal and climatic fluctuations, as well as pathogens. Allocating areas for rouge further creates land use problems.

“To produce EBC-46 sustainably and reliably in the quantities we need,” Wender said, “we really need to go down the synthetic route.”

Making an EBC-46 from scratch

Wender and colleagues realized that a plant-derived phorbol compound was a good starting point for creating EBC-46. Over 7,000 plant species worldwide produce phorbol derivatives, and phorbol-rich seeds are commercially inexpensive. The researchers chose Croton tiglium, commonly known as cleansing croton, an herb used in traditional Chinese medicine.

Wender explains that the first step in preparing for EBC-46 is to mock everyday experience. “You buy a bag of these seeds and it’s not much different than making coffee in the morning,” Wender said. “You grind the seeds and run a hot solvent through them to extract the active ingredient,” in this case a phorbol-rich oil.

After processing the oil to make phorbol, the researchers had to figure out how to overcome the previously insurmountable problem of decorating a part of the molecule called the B ring with carefully placed oxygen atoms. This is necessary so that EBC-46 can interact with PKC and modify the activity of the enzyme in cells.

To guide their chemical and biological research, the researchers relied on instruments from the Stanford Neuroscience Microscopy Service, the Stanford Cancer Institute’s Proteomics/Mass Spectrometry Shared Resource, and the Stanford Sherlock Computer Simulation Cluster.

With this guidance, the team was able to add additional oxygen atoms to the B ring of phorbol, first with the so-called ene (pronounced “een”) reaction, carried out under flow conditions where the reactants mix as they pass together through the tube. The team then introduced other B ring groups in stages and in a controlled manner to achieve the desired atomic arrangement. In total, it took only four to six steps to get the EBC-46 counterparts, and a dozen steps to reach the EBC-46 itself.

Tigilanol tiglat is a natural diterpenoid undergoing clinical trials for the treatment of a wide range of cancers. (CREDIT: Stanford University)

Wender hopes that the much wider availability of EBC-46 and related compounds that affect PKC enabled by this breakthrough approach will accelerate research into potentially revolutionary new therapies.

“As we learn more and more about how cells function, we will learn more about how we can control this function,” Wender said. “This control of functionality is especially important when dealing with cells that go out of control in diseases ranging from cancer to Alzheimer’s.”

Wender is also a member of Stanford Bio-X and the Stanford Cancer Institute, and a Sarafan ChEM-H Fellow.

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Note: Materials provided above by Stanford University. Content can be edited for style and length.

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