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New designed paclitaxel analog kills more cancer cells than natural product

Blacksburg, Va., June 21, 2004 -- A multi-university research team led by Virginia Tech University Distinguished Professor of Chemistry David G. I. Kingston and his collaborators Professor Susan Bane at the State University of New York (SUNY) Binghamton and Professor James P. Snyder at Emory University has succeeded in enhancing the structure of paclitaxel (TaxolTM) to make it more effective in killing cancer cells. They did so by rational design, based on a hypothesis developed by Snyder that paclitaxel adopts a "T-shaped" conformation in its binding pocket on beta-tubulin.

This work is described in the Proceedings of the National Academy of Sciences (PNAS) online early edition the week of June 21 (www.pnas.org), in the article "The bioactive Taxol conformation on (beta)-tubulin: Experimental evidence from highly active constrained analogs," by Research Scientist Thota Ganesh, Graduate Student Rebecca C. Guza and David Kingston, all of Virginia Tech; Research Scientist Rudravajhala Ravindra, Graduate Student Natasha Shanker, and Susan Bane, all of SUNY Binghamton; and Graduate Student Ami Lakdawala and James P. Snyder of Emory, all with the chemistry departments of their respective institutions.

Paclitaxel, a natural compound from yew trees, is the world's best-selling anticancer drug. Several analogs are in clinical trial, with others in preclinical development. One problem that paclitaxel and all its analogs share, however, is that they are all highly complex compounds, and cannot be prepared synthetically in a commercially viable way. "The Holy Grail of paclitaxel research would be to find a compound that had the same biological effect as paclitaxel, but could be prepared synthetically in a few steps," said Kingston. The discovery by the cross-university team marks a significant step along the road to this objective.

Kingston explains that paclitaxel binds to tubulin, a protein mole
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Contact: Susan Trulove
strulove@vt.edu
540-231-5646
Virginia Tech
21-Jun-2004


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