Microcystins – leads for anticancer drugs

In one of my first blog posts I have shortly discussed that the hepatotoxic microcystins, cyclic peptides from cyanobacteria, are currently studied for their potential as leads for anticancer drugs. I also mentioned a poster we presented at the ICNPR 2012 in New York.

Recently, the paper covering our work in this field has been published in PLOS ONE. It describes the cytotoxic potency and the OATP1B1/1B3 transporter selectivity of 23 naturally occurring microcystin congeners. Microcystin variants with cytotoxic OATP1B1/OATP1B3 IC50 ratios that ranged between 0.2 and 32 were found, representing a 150-fold range in transporter selectivity. We found that microcystin structure has a significant impact on transporter selectivity, and thus it should potentially be possible to develop analogs with even more pronounced OATP1B3 selectivity and thus enable their development as anticancer drugs (some cancer types express OATP1B3 and could thus be targeted; for more information see the paper…).

For the figure depicting the chemical structure of microcystins / nodularins I have compiled a list of all congeners described in the literature to date. The data are available at figshare. If you are interested in microcystins you should definitely take a look at this list.

Interestingly, some weeks ago I met a synthetic chemist at a conference who works on a microcystin synthesis, and we started talking about a collaboration. This will be a great opportunity to further explore the chemical space around the microcystins, hopefully leading to derivatives with higher selectivity, potency and better pharmacokinetic properties…

Natural product drug discovery from microalgae

Together with Mark Brönstrup from sanofi-aventis I have written a chapter on “Natural product drug discovery from microalgae” for the book “Microalgal Biotechnology: Integration and Economy“, edited by C. Posten and C. Walter, published by de Gruyter.

I know that this is behind the pay wall – I have signed the author contract before I became Aware of Open… If you want to have a copy of the chapter, just drop me a line. I would be happy about comments on the chapter from anyone interested in this topic.

Edit: What I have learned – Insist on imprimatur. Complicated story why, but the legend of figure 10.8 is wrong and should only read “Mechanism of toxin release from antibody-drug conjugates.”. I have written an email to the publisher and hope that this can be corrected at least in the pdf version of the chapter. After all, it is their mistake that the legend is flawed…

Edit 2: They will correct the figure caption for the pdf file. Thank you, de Gruyter.

How “open” are natural product scientists? Part I – Conference Talks

Four months ago I visited a fantastic conference, the International Conference on Natural Product Research 2012, ICNPR 2012, in New York. It was one of the best conferences I ever visited. I presented two posters there which I later uploaded to figshare (can be downloaded here and here).

Many of the talks were really interesting, and after the conference I contacted 12 speakers if they would share their presentation so that I could have another look at the slides and recapitulate what I had learned.

2 of the scientists answered that they are not willing to share their slides, because some of the material has not been published, yet. Hugh?! How can someone make a publication out of some PowerPoint slides?! And who would be stupid enough to try? And what about those guys in the audience that took pictures of every single slide of every single talk?

Well, at least these two were more polite than the 5 scientists who did not answer at all, even when after a few weeks I kindly remembered them that I had interest to have a second look at their presentations…

This leaves 5 scientists who sent their talks, 3 of them after friendly reminders. Good luck for me that these were the most interesting talks! Funnily enough, 4 of these 5 are professors at the Scripps Institution of Oceanography in San Diego. It might be that American scientists are more willing to share than others; but not all professors from the States I asked did share, though…

Of course this has not been a systematic study of the willingness to share among natural product scientists, but it made me wonder why it is not common standard that all talks are made available to conference attendants after conferences. This would make the experiences of visiting a conference even more pleasant and would enhance the learning effects dramatically.

After making this experience, I decided to share all talks I give, whether people want it or not. 🙂 And I chose figshare as a platform for this. Of course a slide set is less informative than listening to the talks themselves (especially because sometimes I prefer to show only large pictures and spend some time talking around them…), but anyways…

To put my money where my mouth is: Some weeks ago I talked about „Cyanobacteria in Anticancer Natural Product Research” at the annual meeting of the German Pharmaceutical Society 2012 in Greifswald, Germany. Anyone interested can now have a look at the slides at figshare. If you have any questions on the slides or on cyanobacteria in general, don’t hesitate to comment this blog post or directly the slides at figshare.

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… 🙂