Chemical toolkit in the fight against cancer

Making chemical substances solve biological problems: that is Wouter van der Linden’s concise summary of chemical biology. In this way he is making his contribution with chemical substances that can eventually help in the fight against cancer: 'It’s not so much a question of the medicines themselves, but of creating a chemical toolkit to develop those medicines.'

A delicate balance

Wouter van der Linden

Medicines offer a delicate balance. The question is whether it is the cancer cells or the patient who dies first in the therapeutic treatment of cancer. Fortunately, carcinogenic cells are often more vulnerable to inhibitors than other kinds of cells. Bortezomib is an example of such an inhibitor. This medicine has been in use since 2003 against certain forms of leukaemia in third-line cancer therapy where other treatments do not work. However, the side-effects are severe. Researchers are therefore questioning whether the medicine is performing as it should.

Making chemical substances

To deal with this problem Van der Linden has been synthesizing chemical substances under bio-organic laboratory conditions. These substances disable one enzyme activity in the cell but not another. Synthesizing these substances is extremely demanding. Van der Linden is therefore looking for substances that work very selectively or with a certain combination of effects.

Garbage truck

The trick is to fine-tune the inhibitors to such an extent that they attack specific proteins in the cell which are the ones that actually have to be inhibited. Van der Linden’s research designates the protein that has to be inhibited as the “proteasome”. The proteasome is a protein with the crucial function of acting as the cell’s garbage truck, and it works with great precision. If it did not, the cell would expire in its own refuse. The garbage truck proteasome operates by cutting long chains of protein into pieces. There are three ways in which it can do this, depending on where the nick in the chain occurs.

Putting the brakes on the garbage truck

A chemical biologist’s workbench

It is at this point that Van der Linden intervenes. He has developed selective inhibitors for the various ways in which the proteasome can do its “nicking” work. In this way it is possible to establish which of the three actions is appropriate to a given proteasome inhibitor and the degree to which it must be applied. In other words, which clearing-up action the garbage truck should not—or should only partly—carry out so that the cancer cell is destroyed.

Stanford

Van der Linden is keen to delegate these extensive biological tests and share them with his immediate colleagues. Testing is done by means of a culture, or by using mice or human tissue. In this way it is possible to enhance an optimal profile for a proteasome inhibitor in the fight against cancer. Van der Linden will be performing post-doctoral research at Stanford University in California, where pioneering work into the interface between chemistry and biology has been carried out for many years.

Defence

Leiden Institute for Chemistry—Bio-organic synthesis
Wouter van der Linden
“Towards subunit specific proteasome inhibitors”
Date: Thursday 22 December 2011
Time: 3.00 pm
Faculty: Science
Supervisor: Professor H.S. Overkleeft PhD

(22 December 2011/ Mardet van Gennip)

Studying in Leiden

Bachelor

Molecular Science & Technology – Chemistry
Biology

Master

Chemistry
Biology