"We locked the kinase switch in the off position in cancer and in tumor-associated blood vessels," which differs from the way current inhibitors attempt to block active kinases, said David Cheresh, PhD, professor and vice chair of pathology at the UCSD School of Medicine and the Moores UCSD Cancer Center, who led the work.
The new approach employs scaffold-based chemistry combined with supercomputer technology, allowing for rapid screening and development of drugs that are more selective for the tumor. The development and screening processes were used to identify potential drug candidates able to halt a growth signaling enzyme, or kinase, which can foster tumor blood vessel and tumor growth. According to the researchers, the novel approach may become a useful strategy in cancer drug development. The study appears online the week of February 8, 2010, in the Proceedings of the National Academy of Sciences.
In this "rational design approach," Cheresh and his co-workers used the supercomputer at the San Diego Supercomputer Center to custom-design molecules that stabilized the inactive forms of two similar kinases, PDGFRâ and B-RAF – both of which are found to be activated in tumors and in blood vessels that feed tumors. Since PDGFRâ and B-RAF work cooperatively, keeping both turned off causes synergistic effects in tumors, according to Cheresh.
"We custom design a drug for a target that we know either plays a role in blood vessel angiogenesis or tumor invasion," said Cheresh. "By doing this on the computer screen and effectively locking the target in the off position, we can generate selective drugs that are expected to produce minimal side effects. Working with a series of chemical scaffolds, we are able to design specific interactions to fit certain targets in cancer cells."
They tested candidates for their effects on embryonic zebrafish blood vessels, which behave similarly to human cancer blood vessels. Molecules that blocked blood vessel growth in the fish were found to do the same in mice, and Cheresh hopes they will soon be tested in cancer patients.
The drug screen system has several advantages, Cheresh explained. Most standard screens test 400,000 candidates in test tubes to identify a single drug candidate. His group's screening method requires fewer than 100 compounds to be screened because they are rationally designed, look for specific types of targets, and use a zebrafish model, testing molecules in cells, tissues and organs for "physiological relevance." The zebrafish is a popular drug research model because it is transparent and the effects of drugs are easily monitored.
In addition, he said, the rational design approach provides drugs that are more selective, hitting desired targets and yielding fewer side effects.
Co-authors include: Eric A. Murphy, David J. Shields, Konstatin Stoletov, Michele McElroy, Joshua Greenberg, Jeff Lindquist, Lisette Acevedo, Sudarshan Anand, Bharat Kumar Majeti, Breda Walsh, Michael Bouvet, Richard L. Klemke, Wolfgang Wrasidlo, Moores UCSD Cancer Center; Elena Dneprovskaia, TargeGen, Inc., San Diego; Igor Tsigelny, Adrian Saldanha, UCSD; Robert M. Hoffman, Moores UCSD Cancer Center and Anticancer, Inc., San Diego; Peter K. Vogt, The Scripps Research Institute, La Jolla; Lee Arnold, Kinagen, Inc., Encinitas, CA.
Funding support came from the National Cancer Institute and Kinagen, Inc.
The Moores UCSD Cancer Center is one of the nation's 40 National Cancer Institute-designated Comprehensive Cancer Centers, combining research, clinical care and community outreach to advance the prevention, treatment and cure of cancer.
One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie
The dark side of cichlid fish: from cannibal to caregiver
20.04.2018 | Veterinärmedizinische Universität Wien
University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.
Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.
Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...
In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
20.04.2018 | Physics and Astronomy
20.04.2018 | Interdisciplinary Research
20.04.2018 | Physics and Astronomy