Stefan Knapp: Development of chemical probes
Why is it getting harder to develop new drugs?
In the last three or four decades we’ve completely changed the way we develop new drugs. Originally we started out testing molecules – usually natural products that we extract from plants or animals – directly in human or sometimes in an animal model. In the 70s and 80s we gained an understanding of molecular mechanisms that lead to disease, allowing us to rationally design drug molecules that specifically interact with a molecule in the cell, a molecular target. Therefore we start from a very good hypothesis to make a selective drug molecule, avoiding side effects. However, this process needed the development of a lot of new technologies and platforms, from empirical testing to a rational design of a molecule. In cancer, we went from static molecules that in principal kill all cells that grow quickly, to targeting one selective molecule that is deregulated in the cancer. For example, in a certain subtype of leukaemia we target a protein called BCR-ABL, this is an oncogene that drives the growth of this cancer. While the initial chemotoxic approach had a good survival benefit for some patients, many patients died quite quickly during this therapy. Now we can actually cure this disease, by selectively targeting the molecule that is deregulated in this cancer. However the complexity and the large number of molecules that are expressed in a cell (or in a diseased tissue), makes it extremely challenging to select the right target for the development of new medicine.
What approach do you use?
Our approach to finding new targets is to use chemical probes – these are small active molecules that work on disease models that we can then develop on a cellular basis, or maybe in an animal. Molecular probes are not yet drugs but they mimic very efficiently the function of a drug, or the role of a drug in a certain disease. So we can try to study what will happen on a cellular level, if we inhibit our selected target, before we endeavour to go into a very lengthy and costly drug development exercise that sometimes takes up to a decade.
Can you tell us about epigenetic therapy?
Epigenetics is a mechanism that controls the expression of proteins or targets in your cells. Every cell in your body has the same genetic information, so what makes a liver cell a liver cell and an eye cell an eye cell is determined by which genes are actively read – in biology we call this transcribed. This transcription is determined by how we package these genes in a larger assembly, which we call chromatin – this determines the function of a cell. What we’ve also learnt is that transcription is influenced by our environment and can be inherited between generations – sometimes this leads to the development of diseases. With epigenetics therapy, we try to target the epigenetic mechanism that lead to the reading of certain genes, in order to reset this system to a normal state, and thereby try to cure the disease.
What are the most important lines of research that have developed in the past five or ten years?
I’m a structural biologist, the main task of my research is to make images or pictures of these molecular targets from which we want to ultimately develop drugs from. Development of new technologies has led to our ability to make many of these structures. We can now understand entire human gene families, how they’re regulated, and also how we can use this information to make selective drug molecules, which only recognise one in hundreds of these molecules. Making these molecular structures, and making them widely available, enables the rational design of drug molecules.
Why does your line of research matter, why should we put money into it?
In modern society people grow older and older, and that means we need to think about treating degenerative diseases, such as neurodegeneration, for which we have almost no treatments at the moment. That means, if we want to address medical problems in the future we need to make drugs more quickly and also more cheaply, to make them accessible for a large number of patients. What we are trying to do, and how we want to contribute to this process is by, on one hand, developing high quality tool molecules for the evaluation of targets in medicine, and, on the other hand, and similarly importantly, to make these molecules available to a large research community without restricting their use. What we are doing is, we’re trying to work with as many companies in parallel in a very open way, to establish new proof of principals for developing pharmaceuticals. This will enable drug discovery in a very efficient way, at a later stage in the industry.
How does your research fit into Translational Medicine within the Department?
The Nuffield Department of Medicine is one of the largest departments, with a large diversity of different disciplines in medicine. This means I can develop tools, structures and models for the design of molecules for a large community. These are then made available for other scientists to use, who I can collaborate with to develop new therapeutic principals. For this work, the department is an excellent location.