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!
New study from the University of Halle: How climate change alters plant growth
12.01.2018 | Martin-Luther-Universität Halle-Wittenberg
Disarray in the brain
18.12.2017 | Universität zu Lübeck
On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.
We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...
What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...
For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.
Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...
At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.
No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...
Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.
Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...
08.01.2018 | Event News
11.12.2017 | Event News
08.12.2017 | Event News
22.01.2018 | Materials Sciences
22.01.2018 | Earth Sciences
22.01.2018 | Life Sciences