After determining the binding conformation of paclitaxel, US researchers have created an analog with greater in vitro anti-cancer activity than the parent compound, according to findings presented Monday at the annual meeting of the American Chemical Society in Anaheim, California.
“Paclitaxel is known to work by binding tubulin, but the exact spatial orientation of the drug’s flexible side chain was not known,” lead author Dr. David G. I. Kingston, from Virginia Tech University in Blacksburg, told Reuters Health. “Knowing this conformation of paclitaxel is important for two reasons. First, if we could force paclitaxel to assume this shape it could bind tubulin more effectively, possibly enhancing its anticancer effect,” Dr. Kingston said. “Second, you could generate new molecules that mimic this shape.” In collaboration with Dr. Jim Snyder, from Emory University in Atlanta, Dr. Kingston’s team used computer analysis to determine the spatial orientation of the side chain during tubulin binding. The researchers used this information to create several “bridge” analogs, in which the floppy side chain was held in the proper conformation with a molecular bridge.”The best paclitaxel analog we’ve made is actually better than paclitaxel by every criteria we’ve tested. It binds tubulin with much greater affinity and it’s more cytotoxic against two cancer cell lines,” Dr. Kingston said. He said that he is currently seeking funding to test the efficacy of these agents in animal cancer models. (Source: Reuters Health: Anthony J. Brown, MD: Oncolink: April 2004)