The story of the halichondrins

After describing the story of the dolastatins, I thought that also the halichondrins would deserve a post. But I have soon realized that Quintus has already done this very nicely, so that there is no need for me to go into more detail here…

For me it just remains to say that the development of Eribulin from Halichondrin B was a real game changer in the Natural-Product-To-Drug arena.

One of the strongest argument against natural products in drug discovery has always been “It might be a nice hit/lead, but it will never be possible to synthesise such complex compounds economically”. Eribulin simply proves that this is not true. Despite being still rather complex and still having about 20 stereocenters, it is economically feasible to manufacture the compound.

Every decision maker in the natural product sceptic pharmaceutical industry should realise that natural product leads are not that ridiculous after all…

The story of the dolastatins

Two posts ago I have mentioned that the story of the dolastatins deserves an own post. I think it has some nice twists that show how far the way from a bioactivity observed for a biomass extract to an approved drug can be. The following story is part of a book chapter I have recently written. The book is in press, so if you are interested in the complete set of references you will have to be patient until it is published… 😉

(Edit 22.12.2012: The chapter has now been published…)

In 1972, it was discovered that extracts of the sea hare Dolabella auricularia showed pronounced antineoplastic activity. Due to the vanishingly small amounts of active substances in the slug, it was not until 1987 that the structure of the most potent compound in this extract, dolastatin 10, could be elucidated: 1 ton of mollusk biomass was collected from the wild to isolate just 29 mg of dolastatin 10 (structure below)! But honor to whom honor is due – it has later been found that the dolastatins are in fact produced by the cyanobacteria Symploca hydnoides and Lyngbya majuscula, which are part of the sea hare’s diet.

At the time of their discovery, the dolastatins were the most potent antineoplastic substances known, with an ED50 in the picomolar range against a number of cancer cell lines. The dolastatins have been found to bind to tubulin close to the vinca binding site, thus disrupting microtubule function. As the chemical structure of dolastatin 10 is comparatively simple, the development of the compound luckily did not depend on the natural source. The first total synthesis was already described in 1989.

Although the natural dolastatins show remarkable activity in vitro, their in vivo activity as a single agent is not sufficient for direct application as drug substances at dosages where toxic side effects are still tolerable. Numerous synthetic derivatives have been generated, and extensive structure–activity relationships have been established. By 2008, two derivatives, namely tasidotin and soblidotin, had been advanced into phase II clinical trials, but although these compounds were much better tolerated, they still failed concerning their efficacy against the tested cancer types. However, as tasidotin is well tolerated, metabolically stable, water-soluble and orally bioavailable, it is still followed up in other cancer types and in combination therapy.

Monomethylauristatin E (MMAE) is a synthetic dolastatin 10 derivative with pronounced activity and toxicity. Researchers at Seattle Genetics developed a technology to couple MMAE analogs to monoclonal antibodies. The antibodies can be targeted against various cancer cell-specific surface antigens such as e.g. CD30, found on several lymphoma types, Nectin-4, expressed by multiple cancers such as bladder, breast, lung and pancreatic cancer, or glycoprotein NMB, found on breast and melanoma cancer cells. These antibody–drug conjugates (ADCs) are stable in extracellular fluids and relatively non-toxic, because the toxic effector MMAE is covalently bound to the antibody and not liberated. After binding of the antibody to its cancer cell surface antigen, the ADC is internalized into the cell. Inside the lysosomes, the protease-sensitive unit that links antibody and MMAE is cleaved by cathepsin, releasing the toxic agent only in cancer cells expressing the targeted surface antigen, as shown in the following figure.


An ADC successfully exploiting this mechanism is Brentuximab vedotin (Adcetris®), developed by Takeda in collaboration with Seattle Genetics. Brentuximab vedotin targets CD30 and has been approved by the FDA in August 2011 for the treatment of patients with Hodgkin’s lymphoma or systemic anaplastic large cell lymphoma (ALCL). It is the first approved drug that is based on a cyanobacterial metabolite – although the dolastatins have long not been recognized as such…

It took nearly 40 years from the initial bioactive extract to the approved drug. And the way of the bioactive from the cyanobacterium into the slug, from there into the lab and on to total synthesis, and finally to a synthetic derivative coupled to a delivering monoclonal antibody, has not been a very direct one… What a tremendous amount of work this has been!

But what a nice story with a happy end – this is one of the reasons why I love natural product research… 🙂