Using a new bottom-up approach for rational drug design, researchers at Rice University and the University of Texas M.D. Anderson Cancer Center have re-engineered the anti-cancer drug imatinib (Gleevec) to more specifically target one type of cancer while potentially curbing a rare life-threatening cardiotoxic side effect.
Gleevec, developed by Novartis Pharmaceuticals, is FDA-approved for the treatment of chronic myeloid leukemia (CML), Philadelphia-chromosome positive acute lymphoblastic leukemia and gastrointestinal stromal tumors. The drug targets two proteins linked with cancer: C-Kit kinase, a protein that has been tied to gastrointestinal cancer, and Bcr-Abl kinase, a key protein controlling CML.
The re-engineered version of imatinib, a new drug dubbed WBZ-4, was designed at Rice, based on a rational strategy developed by Ariel Fernandez, professor of bioengineering, who said “Our bottom-up design strategy is also broadly applicable to drugs other than imatinib and enables a rational control and reduction of side effects.”
WBZ-4 was designed to target C-Kit without inhibiting the function of Bcr-Abl, which recent imatinib studies have associated with increased risk for heart failure.
“Imatinib actually affects an entire family of kinases beyond those examined here,” said Gabriel Lopez-Berestein, a professor of experimental therapeutics at M.D. Anderson. "This is terrific proof of principle that we can enhance the selectivity of a drug by making a small but significant change in its structure and with precise synthesis and formulation of the new drug. We know exactly how WBZ-4 works. It's a completely novel approach."
In computer models, in vitro assays, and in experimental animals, WBZ-4 was found to be equally effective as regular imatinib at inhibiting C-Kit and halting the growth of GIST cancers. Animal tests also found that the risk of cardiotoxicity was significantly reduced with WBZ-4 compared to imatinib.
"The reason we had set out to identify the basic mechanisms by which anti-cancer drugs can induce cardiotoxicity was the hope that this knowledge could potentially steer drug development away from targets and pathways that would lead to toxicity, but would leave tumor cell killing intact," said Thomas Force, MD, Wilson Professor of Medicine at Thomas Jefferson University.
"Fernandez and co-workers, in this really remarkable piece of work, have proven that this is indeed possible. Their findings will hopefully encourage drug makers to pursue a similar approach of rational drug redesign in the development of new anti-cancer agents, thereby retaining anti-cancer activity with limited toxicity," said Force.
WBZ-4 is not yet available for human testing. A date for human trials has not been set.
The actual incidence of heart failure among patients taking imatinib is not precisely known but it is low, the researchers said. A retrospective study of leukemia patients taking imatinib at M.D. Anderson showed that 1.7 percent of 1,276 patients had symptoms that could have been caused by heart failure.
The National Institutes of Health, the Gulf Coast Center for Computational Cancer Research, the Welch Foundation, the Ovarian Cancer Research Fund and the National Cancer Institute funded the study.