Hello and welcome at the Pharmaceutical Institute at the University of Kiel.

My name is Christian Peiffer and I'm a professor for medicinal chemistry here. In our research, we focus on innovative concepts for cancer treatment. In modern cancer therapy, protein kinases have become important drug targets. These protein kinases are enzymes which phosphorylate signal proteins in signal transduction cascades.

This is one of the most important regulation mechanisms in cells. Sometimes protein kinases may become overactive and this leads to the uncontrolled cellular growth and deformation of the tumor.

It is not surprising that in modern drug discovery programs, protein kinases are an important field. However, some of these kinase inhibitors may cause serious side effects. The goal of our project is the development of a photo-switchable protein kinase inhibitor.

That means the biological activity of such a compound can be controlled by light. This project requires an interdisciplinary approach. Scientists from various life sciences backgrounds work in my group. Now they will show you how their research looks like.

Hi, my name is Rebecca. I've studied pharmacy and now I'm working on my PhD thesis. One of my tasks is molecular modeling. Using 3D software, I can take a closer look at proteins and how drugs bind to their target. For this project, I examined the kinase inhibitor axitinib. It is used for the treatment of kidney cancer.

Axitinib can be switched between two forms by irradiation with UV light. Here you can see the bioactive drenth isomer. It binds to the target and therefore inhibits its function. The other form, the cis isomer, doesn't fit into the binding pocket anymore, so it shouldn't block the enzyme.

Until here, everything just happened on a computer. So to see if our calculations are correct, we have to visit my colleagues in the lab. Welcome to our chemistry lab. My name is Dorian and I'm part of the chemistry team. My job is to develop synthetic strategies for the molecules that have been designed on the computer.

Today, I'll show you a photochemical experiment. This is the kinase inhibitor axitinib in its bioactive trans configuration. For our photochemical and biological testing, we need not only the trans isomer, but also the cis isomer.

To get the cis isomer, we photo switch the double bond by irradiation with UV light. Now we have a mixture of both isomers. Next, we separate them by flash chromatography.

At the end, we collect the purified fractions and evaporate the solvent. Now we have purified our compounds and they are ready for biological testing.

Hello, my name is Boris. I have studied biochemistry and now I'm PhD student in the group. My task is to investigate the impact of the kinase inhibitors on biological tissue. Each cancer consists of thousands of abnormal cells. In our group, we keep different cancer cell lines and culture and use these cells as a tumor model for testing the efficacy of the novel compounds.

Here you can see some cancer cells and culture. These cells are dependent on a certain kinase. For inhibition of this kinase, we hope to suppress the tumor growth. So, what we do now is to add our dissolved inhibitor axitinib to the

cells, incubate them, and then measure the cellular growth in microplates with 96 cells.

We can switch our inhibitor by illuminating the plate with the V LED. As a readout, we measure the number of viable cells. For this, we use a blue dye resazurin.

The viable cells reduce the dye, so it becomes pink. But remaining blue means that the cancer cells are dead. So, you can see here that photo switching to axitinib could be activated and kill the cells. Now you have seen how the life science researchers in our group, pharmacists,

chemists, and biochemists work closely together in a team. By our SFB677 project, we will further develop these photo switchable kinase inhibitors for future applications in cancer therapy.