Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Interaction between two leukemia drugs explained

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:
Weitere Informationen:
- Abstract

Christoph Dieffenbacher | Universität Basel
Further information:

More articles from Life Sciences:

nachricht First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife

nachricht Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Etching Microstructures with Lasers

Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.

This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...

Im Focus: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Ice shelf vibrations cause unusual waves in Antarctic atmosphere

25.10.2016 | Earth Sciences

Fluorescent holography: Upending the world of biological imaging

25.10.2016 | Power and Electrical Engineering

Etching Microstructures with Lasers

25.10.2016 | Process Engineering

More VideoLinks >>>