Reaching into the pocket of the kinases

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Biondi and his colleagues have crystallised the proteins to study the shape of the kinases. Using X-rays, they are able to explore the corresponding proteins in three dimensions. Source: University of Frankfurt

22.07.2011  - 

To regulate themselves, but also to communicate with their surroundings, cells employ specific enzymes known as AGC protein kinases. However, if these are defective it can result in a whole range of diseases. At the Johann Wolfgang Goethe University in Frankfurt am Main, a working group headed by Ricardo Biondi is working on a means of selectively influencing the protein kinases. Aided by the GO-Bio business initiative from the Federal Ministry of Education and Research (BMBF), Biondi is now launching his own company, which will be employing his technique to develop drug candidates for cancer and diabetes.

Cells can respond to external factors via complex pathways that carry information from the outside. If a fault occurs in this system, the cells can no longer properly respond to changes in their environment, and this can result in diseases. Many biotechnological drugs are aimed at influencing these pathways by intercepting the relevant signalling proteins and replacing them with appropriate counterparts.

The X-ray analysis allows the PhosphoSites working group to explore the structure of the protein kinases, and above all the composition of the 'PIF-pocket'.Source: University of Frankfurt

The mouth of the Pacman

Ricardo Biondi has been occupied with a specific class of signalling proteins - the AGC protein kinases - since a stint as a postdoctoral fellow at the prestigious Pasteur Institute in Paris. "From a schematic perspective, the kinases look a bit like Pacman," says Biondi, who since 2008 has worked at the Johann Wolfgang Goethe University in Frankfurt am Main. "Normal inhibitors take effect at the mouth of the Pacman, so to speak."

The 500 known types of protein kinases, on the other hand, differ slightly from each other in the 'mouth'.

The result is that an active ingredient often fits not only to one type of protein kinase - thereby inhibiting it - but often responds to a number of different kinases. "Sometimes that's good, but there are often side effects," says Biondi. His team of researchers are thus focusing not on the 'mouth' of the Pacman, but on a different, hitherto neglected structural region of the enzymes, known as the 'PIF-pocket'. Using small chemical molecules that bind to this pocket, the researchers can influence the activity of the protein kinases. A fact in their favour: not all protein kinases even contain such a pocket, and among the 60 kinases that do, the respective structures differ significantly from each other. This means that the chances are high that a molecule will only affect a single kinase. This high specificity is greatly desirable in pharmaceutical development.

Not only inhibiting, but also activating

Biondi's method has another advantage: Traditional medicines can only inhibit the kinases - a result of their mode of action. With Biondi's approach, the effect of some kinases can even be increased, giving the physicians an even more flexible and powerful toolbox.

In 2007, this idea proved victorious in the second round of the BMBF's GO-Bio founding competition; Biondi was one of ten prize winners (more...). With the subsequent funding, Biondi and his team were for the first time able not only to identify and produce the first activators and inhibitors for the PIF-pocket, but also test them in animal models. Moreover, aided by crystallography, the researchers have built up a detailed microscopic view of the different types of AGC protein kinases, and of the PIF-pockets. "We looked into the protein kinases down to the last atom," explains Biondi. "We now know exactly how the substance interacts with the pocket."

Following the fourth round of the competition in 2011, the funding has now been extended for a further three years. With his newly founded company PSites GmbH and his proprietary screening platform, Biondi is planning to find further appropriate molecules, as well as test the first cancer drug candidates in preclinical studies. At the end of the three-year funding period, it is hoped to have a candidate ready for licensing to a pharmaceutical company for clinical trials and testing on humans. Biondi also envisages active ingredient candidates in the field of diabetes.

Biondi is planning proceed in the same manner as the first candidate as matter of principle. The idea is to develop selected drug candidates to preclinical phase at PhosphoSites GmbH. Cooperations will be sought with pharmaceutical companies for the subsequent development stages. The growth of the company will mean a lot of work for Biondi. Already today, the native Argentinean is rarely home before 11pm. "The day ends at night," he says. "For a long time, I didn't even have an internet connection at home, because I was barely there."