After 3 Decades, Researchers Finally Harness Anti-Cancer Halichondrin Compound in New Drug

Scientists have been trying to synthesize a known anti-cancer compound into a drug to be used for cancer treatments for more than three decades. Now they’ve finally completed their “unprecedented achievement.”

The compound, called halichondrin, exists naturally and can be found in a particular type of sea sponge called Halichondria okadai. It was discovered by a team of researchers based in Japan 33 years ago, but it only occurs in tiny amounts, so it can’t be harvested for use in cancer-fighting drugs. In 1992, a Morris Loeb Professor of Chemistry in the Department of Chemistry and Chemical Biology at Harvard University, Yoshito Kishi, performed the first full synthesis of the compound, but on too small a scale to be of much use.

“In 1992, it was unthinkable to synthesize a gram-quantity of a halichondrin,” says Professor Kishi. “Organic synthesis has advanced to that level, even with molecular complexity that was untouchable several years ago. We are very delighted to see our basic chemistry discoveries have now made it possible to synthesize this compound at large scale.”

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Since the discovery of halichodrins, teams have synthesized simplified forms of the compound for use in cancer treatment, such as the eribulin compound, which was developed in 2010 and made available for treating liposarcoma and metastatic breast cancer. But the search continued for a way to synthesize large batches of the more complex compound.

Throughout all these years, Professor Kishi has continued attempting to recreate the E7130 halichondrin molecule in the lab. Its structure is particularly difficult to replicate, because its 31 chiral centers result in about four billion different ways the experiment can go wrong. That’s why it has taken researchers until now to get it right.

“Due to the very unique structure of the natural product, many people were interested in the mode of action, and the investigators wanted to do a clinical study,” says co-author Takashi Owa, Chief Medicine Creation Officer and Chief Discovery Officer at Eisai’s oncology business group. “But a lack of drug supply prevented them from doing it.”

Lead researcher Professor Kishi and his team have overcome these obstacles and achieved a “total synthesis of […] E7130” in a specimen larger than 10 grams with 99.8 percent purity.

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“It’s a really unprecedented achievement of total synthesis, a special one […]” says Owa. “No one has been able to produce halichondrins on a 10-gram scale — one milligram, that’s it.”

The team will now be able to start a clinical trial with their new treatment. The drug will work by changing the tumor’s microenvironment and increase the number of CD31-positive intra-tumoral endothelial cells.

Now this is what we call determination! Would you work for three decades on a difficult problem like this? We’re sure glad this team did, because it may change the face of cancer care as we know it!

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