Life Science Case Study 1:
Diamond and Drug Development
From the sequencing of the human genome we know that enzymes called kinases are very common in cells, with over 500 protein kinases encoded in the human genome. The “cell cycle” describes how cells replicate themselves and then divide into daughter cells. The regulation of this process of cell growth and cell division becomes uncontrolled in cancer cells. Understanding the protein kinases involved in the cell cycle has led to possible ways for the design of compounds that could be of use in cancer therapy.
One way that you’ve been looking into treatment is in the field of drug design. Have you been analyzing these kinase structures in order to develop drugs?
Yes, essentially. Today, there are 11 compounds that inhibit proteins kinases that have been approved for clinical applications. So we are hoping to do similar things with other protein kinases. It’s quite easy to get a good protein kinase inhibitor and structure can certainly help do that, but to move on from a good inhibitor to a drug is a big step because you have to deal with all the pharmacological properties of how it’s to be delivered. Making sure it’s non toxic, making sure it does what it’s supposed to do etc. But from structure we can certainly contribute to the design of small molecules that will regulate kinase activity.
How do you go about using the Diamond synchrotron to study the structure of these kinases?
We use the technology of protein crystallography. We are able to prepare our protein kinase in the laboratory using recombinant DNA expression methods. The kinase is then crystallized so that all the molecules are all lined up, each one is in the exactly same orientation as its neighbours. We then record the X-ray diffraction pattern from the crystal; that is how the X-rays are scattered by the crystal lattice and from that scattering pattern we can work back to the structure of the individual molecule. Frequently the more interesting your biological molecule is from the biology point of view, the more likely it is to produce very small crystals. We are limited by the brightness of the X-ray sources in our laboratories; these are not bright enough to allow recording from very small crystals. Typically, in the laboratory, we need crystals of the order of 0.2 mm, but with the Diamond Light Source we have a very much brighter source of X-rays and also beautifully designed beamlines that can run automatically to collect data. This has made is possible to collect data from more problematic crystals sometimes as small as 10 µm (0.01 mm) and also to collect data with better precision so that then we can obtain a more precise structure.