A new study highlighted on the cover of this week's issue of Cancer Research finds that the anti-cancer drug Gleevec® is far more effective against a drug-resistant strain of cancer when the drug wraps the target with a molecular bandage that seals out water from a critical area. The research appears as a priority report in the journal's May 1 issue.
The wrapping version of the drug – known as WBZ-7 – was created, produced and tested by three research teams, one headed by Ariel Fernandez from Rice University and the other two headed respectively by William Bornmann and Dr. Gabriel Lopez-Berestein from the University of Texas M. D. Anderson Cancer Center in Houston. The work sprang from a new collaborative partnership between the two institutions. In laboratory studies, WBZ-7 was found to be effective against a form of gastrointestinal cancer that has developed a resistance to imatinib, the drug sold under the brand name Gleevec®.
Imatinib is one of the most effective of a new generation of cancer drugs that are designed to attack cancer cells and leave healthy cells unharmed. Imatinib targets a protein called KIT that plays a role in cell reproduction. In healthy cells, KIT is active only on rare occasions, but in some cancers the protein is always "on," acting as a biochemical catalyst that spurs cancer cells to constantly reproduce.
"The re-engineered version of imatinib accomplishes three things," said Rice bioengineering professor Ariel Fernandez, who designed the modified drug. "It binds with KIT. It binds with the most effective imatinib-resistant version of KIT. And finally, it binds in a way that ensures that any further version of KIT that becomes resistant to WBZ-7 will no longer be effective as a catalyst for cell reproduction."
Fernandez and his Rice colleagues – postdoctoral researcher Alejandro Crespo and graduate student Xi Zhang – developed the wrapping Gleevec® variant WBZ-7. The wrapping prototype is a kind of molecular bandage that's designed to keep water molecules from getting near the "active site" of KIT – the part of the protein that imatinib targets.
"Like virtually all proteins, KIT has packing defects that leave some hydrogen bonds poorly shielded from water attack," Fernandez said. "These bonds, which are called dehydrons, are in the twilight zone between order and disorder."
In KIT, there is a dehydron near the active site that plays a key role in drug resistance. WBZ-7 seals off this dehydron.
Fernandez said WBZ-7 is identical to imatinib, save for the addition of four atoms – a carbon and three hydrogens – at a key point. Though the change appears to be minimal at first glance, finding a method to synthesize the compound was complex and challenging, Fernandez said. The task fell on Bornmann, a director of the Center for Targeted Therapy's Translational Chemistry Service, and his colleagues Shimei Wang and Zhenghong Peng – who dubbed the compound WBZ-7 based on their initials and the fact that it was the seventh compound they'd made together.
Following the drug's synthesis, a second team of M. D. Anderson researchers, led by Lopez-Berestein, a professor in the Department of Experimental Therapeutics, and including Angela Sanguino and Eylem Ozturk, embarked on a comprehensive testing program. In the first stage of testing, WBZ-7's effects were tested against more than 250 catalytic proteins called kinases, which are in the same class of proteins as KIT, to make sure the drug would not have unintended consequences. Finally, a range of in vitro tests were conducted. The tests confirmed that WBZ-7 was just as effective against both non-resistant and drug-resistant strains of gastrointestinal cancer cells.
WBZ-7 is not yet available for human testing, and a date for human trials has not been set. Fernandez said the research team is preparing for the next phase of testing in laboratory animals.
Jade Boyd | EurekAlert!
The Great Unknown: Risk-Taking Behavior in Adolescents
19.01.2017 | Max-Planck-Institut für Bildungsforschung
A sudden drop in outdoor temperature increases the risk of respiratory infections
11.01.2017 | University of Gothenburg
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Awards Funding
20.01.2017 | Materials Sciences
20.01.2017 | Life Sciences