A novel anti-cancer drug development strategy has resulted in new drug that has the potential to stop kidney and pancreatic tumours from growing, say scientists at the University of California, San Diego.
Their study in mice showed that the drug binds to a molecular 'switch' found in cancer cells and cancer-associated blood vessels to keep it in the 'off' position.
David Cheresh, professor and vice chair of pathology at the UCSD School of Medicine and the Moores UCSD Cancer Center, who led the study, said: "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.
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 tumour.
The development and screening processes were used to identify potential drug candidates able to halt a growth signaling enzyme, or kinase, which can foster tumour blood vessel and tumour growth.
According to the researchers, the novel approach may become a useful strategy in cancer drug development.
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, PDGFRB and B-RAF - both of which are found to be activated in tumours and in blood vessels that feed tumours.
Since PDGFRB and B-RAF work cooperatively, keeping both turned off causes synergistic effects in tumours, according to Cheresh.
"We custom design a drug for a target that we know either plays a role in blood vessel angiogenesis or tumour 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," Cheresh added
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 study appears online the week of February 8, 2010, in the Proceedings of the National Academy of Sciences.