Harvard University chemists have achieved what a new paper calls a landmark in drug discovery with the synthesis of halichondrin, a potent anti-cancer agent found naturally in sea sponges. The halichondrin anti-cancer agent class of molecule is so complex that it had never been synthesized on a meaningful scale in the lab \u2014 until now.<\/p>\n
Researchers at Harvard’s Department of Chemistry and Chemical Biology have synthesized sufficient quantities of E7130, a drug candidate from the halichondrin class, to enable for the first time rigorous studies of its biological activity, pharmacological properties, and efficacy. These studies were conducted in collaboration with researchers at Japanese pharmaceutical company Eisai.<\/p>\n
Halichondrin is a naturally occurring compound found in sea sponges, long recognized for its potent anti-cancer properties in mouse studies. The halichondrin anti-cancer agent class has been of scientific interest for over three decades, but its extraordinary molecular complexity made large scale synthesis virtually impossible \u2014 until this breakthrough.<\/p>\n
The complete E7130 molecule is particularly challenging to replicate because it has 31 chiral centers \u2014 asymmetrical points that must each be correctly oriented. In other words, there are roughly 4 billion ways to get it wrong.<\/p>\n
The Kishi Lab’s results, driven to completion through an intense three year research collaboration with Eisai, are published in Scientific Reports, an open access Nature journal. The paper reports the total synthesis of the halichondrin anti-cancer agent E7130 \u2014 11.5 grams of it, with 99.81% purity \u2014 and characterizes its mode of action.<\/p>\n
In preclinical studies, the research team identified E7130 not only as a microtubule dynamics inhibitor, as was previously recognized, but also as a novel agent to target the tumor microenvironment. Specifically, 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 transformation to malignancy.<\/p>\n
“We spent decades on basic research and made very dramatic progress,” said Professor Kishi, whose laboratory has received significant and sustained support from the National Cancer Institute of the National Institutes of Health<\/a> since 1978 to study the synthesis of natural products.<\/p>\n When the natural product was first identified 33 years ago by Japanese researchers, it sparked immediate interest. Over time, NCI investigators testing tiny amounts of the halichondrin anti-cancer agent recognized that it was affecting the formation of microtubules, which are essential to cell division.<\/p>\n In 1992, Kishi and colleagues achieved the first total synthesis of a halichondrin molecule \u2014 halichondrin B. The process required a sequence of more than 100 chemical reactions and produced less than 1% overall yield. Despite this, it was a major achievement. A simplified version of that molecule, eribulin, became a drug to treat metastatic breast cancer and liposarcoma, now marketed by Eisai.<\/p>\n “In 1992, it was unthinkable to synthesize a gram quantity of a halichondrin,” Kishi noted, “but three years ago we proposed it to Eisai. Organic synthesis has advanced to that level, even with molecular complexity that was untouchable several years ago.”<\/p>\n The halichondrin anti-cancer agent E7130 has undergone unusually 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 to Eisai. The company hopes to begin a second clinical trial in the United States in due course.<\/p>\n Takashi Owa, Chief Medicine Creation Officer and Chief Discovery Officer for Eisai’s oncology business group, described the achievement as unprecedented. “No one has been able to produce halichondrins on a 10 gram scale \u2014 one milligram, that’s it. They have completed a remarkable total synthesis, enabling us to initiate a clinical trial of E7130.”<\/p>\n The speed of this development \u2014 from discovery stage to clinical development of such a complex molecule in just three years \u2014 reflects the power of close academia and industry collaboration.<\/p>\n Vivian Berlin, Managing Director of Strategic Partnerships in Harvard’s Office of Technology Development, noted that the collaboration between Harvard and Eisai is an example of academia and industry working together to accelerate the development of a new class of therapeutics that may address important unmet medical needs.<\/p>\n This kind of partnership is exactly what drives breakthroughs from the laboratory into patient care. Understanding how discoveries like this halichondrin anti-cancer agent move through the development pipeline requires understanding clinical trials. Our introduction to clinical trials<\/a> provides a comprehensive overview of how Phase I through Phase IV studies work and why they matter.<\/p>\nDecades of Progress Leading to This Moment<\/h3>\n
From Lab to Clinical Trial<\/h3>\n
The Power of Academic and Industry Collaboration<\/h3>\n