The discovery of chemists in the synthesis advances a powerful anti-cancer agent

This is a feat that has been underway for three decades: Harvard University chemists have realized what a new document calls "a milestone in drug discovery" with the total synthesis of halichondrin. Known to be a potent anti-cancer agent in mouse studies and found naturally in sea sponges – though never in minute amounts – the class of halichondrin molecules is so terribly complex that it does not have much effect. has never been synthesized significantly in the laboratory.

Researchers led by Yoshito Kishi, chemistry professor Morris Loeb, Emeritus, from the Harvard Chemistry and Chemical Biology Department, have now synthesized sufficient quantities of E7130, a drug candidate in the halichondrin class, to allow for the first time to rigorously study its biological activity, its pharmacological properties and its effectiveness, all conducted in collaboration with researchers from the Japanese pharmaceutical company Eisai.

The molecule has undergone unusually fast development and is already undergoing a Phase I clinical trial in Japan under license from Harvard's OTD (Office of Technology Development) in Eisai. The company hopes to start a second clinical trial in the United States in due course.

The results of the Kishi Lab, completed after an intense three-year research collaboration with Eisai, are published today in Scientific reports, a journal Nature open access. The article describes the total synthesis of the extremely potent molecule of the E7130 halichondrin, of which it contains 11.5 grams, of a purity of 99.81%, and characterizes the mode of the molecule. ;action. In preclinical studies, the research team identified him not only as an inhibitor of microtubule dynamics, as previously recognized, but also as a new agent for targeting the microenvironment of the tumor.

"We have devoted decades to basic research and made dramatic progress," says Kishi, whose lab has since 1978 enjoyed significant and sustained support from the National Cancer Institute (NCI) of the National Institutes of Health. in order to study the synthesis of natural products. .

The structure of the complete molecule E7130 obtained by total synthesis is particularly difficult to reproduce because it has 31 chiral centers, asymmetrical points which must each be correctly oriented. In other words, there are about 4 billion ways to go wrong.

When the natural product was identified for the first time 33 years ago by Japanese researchers, it aroused immediate interest. "They then realized that the halichondrins looked extremely powerful," recalls Takashi Owa, Ph.D., who is responsible for creating the drug and responsible for discovery for the company's group of companies. Oncology of Eisai, and co-author of the document. Over time, NCI researchers who have tested tiny have recognized that it affects the formation of microtubules, essential for cell division. "Due to the very unique structure of the natural product, many people have become interested in the mode of action, and the researchers wanted to conduct a clinical study," says Owa, but a lack of drug supply prevented them. Unfortunately, 30 years have passed, but Professor Kishi is a pioneer in this area. "

Over the years, the Kishi Lab has perfected convergent synthesis methods, which make it possible to assemble complex molecules from subunits rather than construct them in a linear fashion. Another innovation, now known as the Nozaki-Hiyama-Kishi reaction, protects highly reactive functional groups during assembly. And in 1992, Kishi and his colleagues performed the first total synthesis of a halichondrin molecule (Halichondrin B). The process required a sequence of more than 100 chemical reactions and produced an overall yield of less than 1%. However, this was a major achievement, and a simplified version of this molecule, eribulin, has become a drug for the treatment of metastatic breast cancer and liposarcoma, now marketed by Eisai. Since then, Kishi's laboratory has been engaged in fundamental research on organic synthesis, including the discovery and development of new reactions that can be used at an advanced stage of synthesis.

"In 1992, it was unthinkable to synthesize a gram amount of a halichondrin," says Kishi, "but three years ago we proposed it to Eisai." Organic synthesis has reached that level, even with untouchable molecular complexity many years ago, we are pleased to see that our discoveries in basic chemistry have made it possible to synthesize this compound on a large scale. "

"It's an unprecedented achievement in total synthesis, a special achievement," says Owa. "Nobody was able to produce halichondrins on a 10 gram scale – one milligram, that's all – they completed a remarkable total synthesis, allowing us to launch a clinical trial of E7130."

The teams Scientific reports The article describes the results of studies conducted in vitro and in vivo, on animal models, which allowed to better understand the complex mode of action of the molecule. The team showed that E7130 could increase CD31-positive and intratumoral endothelial cells and reduce cancer-associated alpha-SMA-positive fibroblasts, components of the tumor microenvironment that may be involved in transformation into malignancy.

"Professor Kishi's expertise has provided us with a unique and exciting opportunity to test the molecule in our systems," said Owa. "I have never experienced this type of very effective, fast and successful collaboration, only three years of collaboration has made it possible to move from the discovery to the clinical development of such a complex molecule, endowed with mechanism and a very unique mode of action, for me it is a sort of review of drug development. "

"The collaboration between scientists from Eisai and Harvard is an example of collaboration between academia and industry to accelerate the development of a new class of drugs likely to respond to important unmet medical needs, "says Vivian Berlin, Managing Director of Strategic Partnerships at Harvard OTD. . "The spirit of collaboration and the transparency of the relationship have contributed immensely to the success of the project."

"Without OTD," adds Owa, "this collaboration would never have happened." Harvard OTD was a kernel for industry and Harvard researchers, and to facilitate discussions on how to build a win-win relationship. "