This cancer-fighting molecule took 50 years to build

MIT scientists have achieved the first-ever lab synthesis of verticillin A, a complex fungal compound discovered in 1970. Its delicate structure stalled chemists for decades, despite differing from related molecules by only two atoms. With the synthesis finally complete, researchers created new variants that showed strong activity against a rare pediatric brain cancer. The breakthrough could unlock an entire class of previously unreachable cancer-fighting molecules.

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MIT chemists have produced verticillin A in the lab for the first time. This fungal molecule was identified more than 50 years ago and has drawn attention for its potential as an anticancer agent.

Verticillin A is notoriously hard to build because of its intricate chemical architecture. Even compared with closely related compounds, it proved far more challenging to synthesize, despite differing by only a couple of atoms.

"We have a much better appreciation for how those subtle structural changes can significantly increase the synthetic challenge," says Mohammad Movassaghi, an MIT professor of chemistry. "Now we have the technology where we can not only access them for the first time, more than 50 years after they were isolated, but also we can make many designed variants, which can enable further detailed studies."

In lab tests using human cancer cells, one verticillin A derivative stood out against a pediatric brain cancer known as diffuse midline glioma. The researchers emphasize that additional testing is needed to assess whether it could eventually be useful in the clinic.

Movassaghi and Jun Qi, an associate professor of medicine at Dana-Farber Cancer Institute/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, are the senior authors of the study, published in the Journal of the American Chemical Society. Walker Knauss PhD '24 is the paper's lead author. Xiuqi Wang, a medicinal chemist and chemical biologist at Dana-Farber, and Mariella Filbin, research director in the Pediatric Neurology-Oncology Program at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, are also authors.