It is a performance for three decades: Harvard University chemists have achieved what a new paper calls a "milestone in drug research" with the overall synthesis of halichondrin. Known to be a strong anticancer agent in mouse studies and found naturally in seaweed – albeit in small quantities – is the molecule's halichondrix class so profoundly complex that it had never been synthesized on a meaningful scale in the lab.
Researchers led by Yoshito Kishi, Morris Loeb Professor of Chemistry, Emeritus at Harvard's Department of Chemistry and Chemical Biology, has now synthesized sufficient amounts of E7130, a drug candidate from the halichondrink class, for the first time to enable rigorous studies of its biological activity, pharmacological properties and efficacy, all of which are carried out in collaboration with researchers in the Japanese pharmaceutical company Eisai.
The molecule has undergone exceptionally rapid development and is already being tested in a Phase I clinical trial in Japan, under a license from Harvard's Office of Technology Development (OTD) to Eisai. The company hopes to start another clinical trial in the US over time.
Kishi Lab's results, which are driven to completion through an intensive three-year research collaboration with Eisai, are published today in Scientific Reports an open access Nature Journal. The paper reports the overall synthesis of the highly potent halichondrin molecule E71
"We have spent decades on basic research and made very dramatic progress," said Kishi, whose laboratory since 1978 has received substantial and sustained support from the National Cancer Institute (NCI) of the National Institutes of Health to study the synthesis of natural products. The structure of the complete E7130 molecule derived from total synthesis is particularly challenging to replicate because it has 31 chiral centers, asymmetric points, each of which must be properly oriented. In other words, there are about 4 billion ways to get it wrong.
When the natural product was first identified 33 years ago by Japanese scientists, it was instant interest. "At that time, they realized that the halichondrines were so strong," recalls Takashi Owa, PhD, Chief Medicine Creation Officer and Chief Discovery Officer for Eisai's oncology business group and a co-author of the paper. Over time, NCI investigators recognized small amounts of it affecting microtubule formation, which is crucial for cell division. "Because of the very unique structure of the natural product, many were interested in the behavior and the investigators wanted to do a clinical examination," Owa explains, "but lack of medication prevented them from doing so. 30 years have passed, unfortunately, but Prof. Kishi is a pioneer in this field. "
Over the years, Kishi Lab has developed methods of convergent synthesis that allow the assembly of complex molecules from subunits, rather than constructed linearly. Another innovation, now known as the Nozaki-Hiyama-Kishi reaction, protected the highly reactive functional groups as they were assembled. And in 1992, Kishi and colleagues achieved the first overall synthesis of a halichondrin molecule (halichondrin B). The process required a sequence of more than 100 chemical reactions and produced less than a total yield of 1%. However, it was an important achievement, and a simplified version of the molecule, eribulin, became a drug for the treatment of metastatic breast cancer and liposarcoma, which is now marketed by Eisai. Since then, Kishi's laboratory has been involved in basic research on organic synthesis, including the discovery and development of new reactions that can be used in a late synthesis stage.
"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 progressed to this level, even with molecular complexity that was motionless several years ago. We are very pleased to see that our basic chemistry challenges have made it possible to synthesize this compound on a large scale. "
" It is a truly unprecedented achievement of total synthesis, a special one, " says Owa. "No one has been able to produce halichondrines on a scale of 10 grams – one milligram, that is. They have carried out a remarkable total synthesis that allows us to initiate a clinical trial of E7130."
Scientific Reports describe the results of in vitro and in vivo studies in animal models illustrating the complex mode of action of the molecule. The team showed that E7130 can increase intratumoral CD31-positive endothelial cells and reduce alpha-SMA-positive cancer-associated fibroblasts, components of the tumor microenvironment that may be involved in the conversion to malignancy.
"Prof. Kishi's expertise provided us with such an exciting and unique opportunity to test the molecule in our systems," Owa says. "I have never experienced this kind of highly effective and fast and successful collaboration. Just a three-year collaboration took it from the discovery stage to the clinical development of such a complex molecule that has a very unique mechanism and mode of action. Development. "
" The collaboration between researchers at Eisai and Harvard is an example of academia and industry working together successfully to accelerate the development of a new class of therapeutic agents that can address important unchanged medical needs. ", says Vivian Berlin, CEO of strategic partnerships at Harvard OTD. "The spirit of cooperation and transparency in the relationship contributed tremendously to the success of the project."
"Without OTD," Owa adds, "this collaboration could never have happened. Harvard OTD has been at the heart of the bridging industry and Harvard researchers, and facilitated discussions on how to build a win-win relationship."  ###
Research for the new publication entitled "A milestone in drug discovery based on complex natural product syntheses" was conducted jointly by researchers at Harvard and Eisai. Harvard OTD has protected intellectual property rights in this project, which is now exclusively licensed to Eisai for the commercial development of therapy.