Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Interaction between two leukemia drugs explained

05.11.2013
Currently no treatment option is available for five percent of patients suffering from chronic myelogenous leukemia, since they have developed resistance to conventional medications.

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
Lukasz Skora, Jürgen Mestan, Doriano Fabbro, Wolfgang Jahnke, and Stephan Grzesiek.
NMR reveals the allosteric opening and closing of Abelson kinase by ATP-site and myristoyl pocket inhibitors.

Proceedings of the National Academy of Sciences PNAS, Published online 4 November 2013.

Further Information
Prof. Dr. Stephan Grzesiek, Biozentrum of the University of Basel, Tel.: +41 61 267 21 00, E-Mail: stephan.grzesiek@unibas.ch
Weitere Informationen:
http://www.pnas.org/content/early/2013/11/01/1314712110.abstract
- Abstract

Christoph Dieffenbacher | Universität Basel
Further information:
http://www.unibas.ch

More articles from Life Sciences:

nachricht O2 stable hydrogenases for applications
23.07.2018 | Max-Planck-Institut für Chemische Energiekonversion

nachricht Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Future electronic components to be printed like newspapers

A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.

The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

The Maturation Pattern of the Hippocampus Drives Human Memory Deve

23.07.2018 | Science Education

FAU researchers identify Parkinson's disease as a possible autoimmune disease

23.07.2018 | Health and Medicine

O2 stable hydrogenases for applications

23.07.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>