Aizpea Zubia and Fernando Cossío are the visible heads of the team from the Faculty of Chemistry of the University of the Basque Country that was awarded the 10th Research Prize granted by the Esteve Foundation. Among 45 nominated articles, the development of a family of synthetic molecules able to restrain liver metastases by 50% in experimental melanoma was considered by the international jury as the best pharmacological work published by a Spanish team between 2004 and 2005. Its merit: designing inhibitors that trick cancer cells by imitating the protein properties that allow these cells to invade healthy tissue.

How do you manage to trick cancer cells?

Fernando Cossío: Cancer cells have membrane proteins which provide anchorage to healthy cells. The idea is to design a small molecule that gathers all the geometric and electronic properties of the active part of the healthy cell’s ligand. These small molecules are introduced at the protein’s binding site used by the cancer cell for metastasis and prevent their anchorage.

The results of your work suggest that more than 50% of liver metastases were blocked in experimental melanoma (the so-called B16). Is this applicable to other types of cancer?

FC: Yes it is, in any process involving VLA-4/VCAM-1 interaction. We are also developing new families of inhibitors against other integrins such as LFA-1, in order to interrupt or hinder LFA-1/ ICAM-1 interaction using similar methodologies. No matter how different molecules are, they work in a very similar way. In this case, the advantage is that both the integrin structure and that of its ligand are known, which provides far greater precision to our work. In former research, conversely, knowing only the ligand’s structure made it all more complicated technically.

Is it optimistic to consider a possible future medicament at such an early stage?

Aizpea Zubia: This first phase has included in vitro and in vivo assays in mice. However, beside being active against the therapeutic target, these medicaments must meet many other requirements, such as administration being preferably by oral route, suitable pharmacokinetic and pharmacodynamic properties, etc. All this is pending and we’ll have to see if each and every condition required to reach the market is overcome.

How complicated was it to find this type of molecules?

FC: Mimicking the properties of the active loop of the natural ligand of VCAM-1 was not too complicated. On the one hand, there was an acidic residue which we thought acted as some sort of electrostatic beacon that rapidly attracted integrin. We also thought that introducing this electrostatic beacon into a relatively rigid hydrophobic environment would offer good opportunities for having a reasonably powerful inhibitor of the interaction. On the other hand, we were then conducting a very intensive cycloaddition program to obtain 5-link rings. These rings are very well balanced in terms of flexibility and rigidity –they are neither too flexible nor too rigid– and thus provide good frameworks where suitable, interesting groups may be hanged. Putting the two together left a relatively simple margin of action.

What are the differences between your type of chemistry and more classical ones, i.e. based on compound elaboration, etc?

FC: Probably, our key differentiating feature is the synergy between theory and experiment. There are optimal, top-level groups of synthetic chemists, and the same applies to computational chemists. However, both are usually highly specialized, very powerful groups that work separately. We do both things at the same time. In fact, before performing the cycloaddition reactions included in our study, we had previously studied the reaction, the transition states and the mechanism, and we already knew that only one product had to be formed. We went to the lab knowing what we wanted. Roughly, our differentiating feature is that, before initiating experimentation, we acquire in-depth knowledge of the reactions we intend to develop and of the novelties we wish to add in order to know whether they will or will not work.

Are there many groups in Spain working this way?

FC: Quite a few. At any rate, many more than when we started in the early nineties. Like I said, there were top-level synthesis groups and top-level computational groups, but very few mixed the two approaches. Now, this mixing approach is gaining popularity.

What do you think about the collaboration between chemists and biologists?

FC: I think it is a very positive one. In fact, the project was born out of dialog with physicians and cell biologists. It was Professor Vidal Vanaclocha who had developed a metastasis model involving VLA-4 VCAM-1 interaction and who stated the biological nature of the problem. We were also lucky to work with a biotech company, Dominion Pharmakine, which co-funded a good part of the project and also performed biological experiments. This was a very positive synergic interaction between chemists, physicians and biologists.

Your work has also won an entrepreneurship prize on account of combining university research and enterprise. Do you think this combination will ensure the survival of university research in the future?

FC: I think it will, because these two approaches provide a sound distribution of technological risks. While an academic institution may face quite risky synthetic methodologies or designs, a biotech company –much more agile in carrying out projects– may focus all its power on any worthy results. I think that this distribution of novelty, technological risk and transition effectiveness offers the best of both worlds. However, because universities are just beginning to develop these approaches, the coupling processes of these two types of institutions are not always easy. But I believe that this is the path to the future as far as innovating, high-risk projects are concerned.

Finally, how did your team feel about winning the 10th Research Prize granted by the Esteve Foundation?

AZ: Our team was greatly honored to receive this prize, which encourages us to carry on with future works.

FC: Because research is quite a stressing and solitary activity, such an acknowledgement gave us a great boost of confidence to help us through the inevitable hard times of a research process, which is highly uncertain and where negative results are more frequently obtained than positive ones.

Application of stereocontrolled stepwise [3+2] cycloadditions to the preparation of inhibitors of alpha(4) beta(1)-integrin-mediated hepatic melanoma metastasis, published in the German journal Angewandte Chemie on 13 April 2005, is the article that was awarded the 10th Research Prize granted by the Esteve Foundation and endowed with 18,000 Euros. The awards ceremony was held on 11 July 2005 at the Edificio Korta of the Guipúzcoa Campus of the University of the Basque Country.

The international jury, composed of Meindert Danhof, from the Leiden/Ámsterdam Research Center for Drug Research, Sergio Erill, from the Esteve Foundation, and Patrick du Souich, from the University of Montreal, awarded the prize and the following honorable mentions:

–PI3Kγ inhibition blocks glomerulonephritis and extends lifespan in a mouse modelo of systemic lupus, Barber DF, Nature Medicine 2005;11 (9)

–Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease, Bosch F, The Journal of Clinical Investigation 2004; 113: 1149-1157