"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.
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