Prof. Stephan Grzesiek’s group at the Biozentrum of the University of Basel, in collaboration with Dr. Wolfgang Jahnke and colleagues from Novartis, has investigated the combined action of two different compounds against this form of leukemia.
Structure of the open tyrosin kinase-imatinib complex.
They have been able to explain at the atomic level, how both substances alter the structure of an enzyme and how their combination potentially can overcome drug resistance. Their findings are published in the current issue of PNAS.
Chronic myeloid leukemia (CML) is a form of blood cancer based on a genetic disorder that leads to the overproduction of white blood cells. Ninety-five percent of affected patients can be treated successfully with the Novartis drug imatinib, also known as Gleevec®. Imatinib is an inhibitor that blocks the ATP-binding site of the tyrosine kinase Abl in affected blood cells, thereby suppressing their overactivity. Consequently, the pathological overproduction of leucocytes is stopped and the blood count normalizes.
Five percent of all patients are not cured by imatinib
However, in five percent of CML patients, typically in an advanced stage of the disease, imatinib and similar ATP-binding site inhibitors are not effective. This resistance against treatment is caused by a mutation at the ATP-binding site, which prevents the inhibitors from inactivating the enzyme. Currently, new treatments are being developed to help such resistant patients. One approach is based on the combination of ATP-binding site inhibitors with so-called allosteric inhibitors, which bind to a different location.
Why the drug combination works in resistant CML
Why such a combination of the two inhibitor types works in an animal model has now been explained by Prof. Stephan Grzesiek‘s team at the Biozentrum of the University of Basel and Dr. Wolfgang Jahnke from Novartis, by a structural analysis using nuclear magnetic resonance spectroscopy (NMR). Under physiological conditions, the tyrosine kinase Abl is found in two different spatial structures - an open and a closed state - which exist in a delicate equilibrium. The researchers have shown that the binding of imatinib unexpectedly shifts this equilibrium to the open state. Although the enzyme itself is inhibited in this state, it can be more easily re-activated through other tyrosine kinases. The allosteric inhibitor GNF-5, however, stabilizes the closed, inactivated state, and even recloses the imatinib-induced open state.
“Thus the inhibitory potentials of both drugs add together to suppress the kinase activity. Our structural analysis enables us to understand why GNF-5 contributes to overcome imatinib resistance,” explains Lukasz Skora, a former postdoc from Stephan Grzesiek’s lab. These results provide a detailed insight into how Abl kinase behaves under the influence of inhibitors, giving hope for a successful combination therapy.Original Citation
Proceedings of the National Academy of Sciences PNAS, Published online 4 November 2013.Further Information
Christoph Dieffenbacher | Universität Basel
Family of crop viruses revealed at high resolution for the first time
15.10.2019 | John Innes Centre
Receptor complexes on the assembly line
15.10.2019 | Albert-Ludwigs-Universität Freiburg im Breisgau
Researchers at Ludwig-Maximilians-Universitaet (LMU) in Munich have explored the initial consequences of the interaction of light with molecules on the surface of nanoscopic aerosols.
The nanocosmos is constantly in motion. All natural processes are ultimately determined by the interplay between radiation and matter. Light strikes particles...
Particles that are mere nanometers in size are at the forefront of scientific research today. They come in many different shapes: rods, spheres, cubes, vesicles, S-shaped worms and even donut-like rings. What makes them worthy of scientific study is that, being so tiny, they exhibit quantum mechanical properties not possible with larger objects.
Researchers at the Center for Nanoscale Materials (CNM), a U.S. Department of Energy (DOE) Office of Science User Facility located at DOE's Argonne National...
A new research project at the TH Mittelhessen focusses on the development of a novel light weight design concept for leisure boats and yachts. Professor Stephan Marzi from the THM Institute of Mechanics and Materials collaborates with Krake Catamarane, which is a shipyard located in Apolda, Thuringia.
The project is set up in an international cooperation with Professor Anders Biel from Karlstad University in Sweden and the Swedish company Lamera from...
Superconductivity has fascinated scientists for many years since it offers the potential to revolutionize current technologies. Materials only become superconductors - meaning that electrons can travel in them with no resistance - at very low temperatures. These days, this unique zero resistance superconductivity is commonly found in a number of technologies, such as magnetic resonance imaging (MRI).
Future technologies, however, will harness the total synchrony of electronic behavior in superconductors - a property called the phase. There is currently a...
How do some neutron stars become the strongest magnets in the Universe? A German-British team of astrophysicists has found a possible answer to the question of how these so-called magnetars form. Researchers from Heidelberg, Garching, and Oxford used large computer simulations to demonstrate how the merger of two stars creates strong magnetic fields. If such stars explode in supernovae, magnetars could result.
How Do the Strongest Magnets in the Universe Form?
02.10.2019 | Event News
02.10.2019 | Event News
19.09.2019 | Event News
15.10.2019 | Materials Sciences
15.10.2019 | Interdisciplinary Research
15.10.2019 | Life Sciences