Houston, TX - Researchers have gone back to the drawing board with the blockbuster drug imatinib (Gleevec, Novartis) and are working to eliminate its adverse effects [1]. It is Novartis's second-best-selling product, with sales of $2.55 billion last year. But the popular chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST) treatment has been known for several serious adverse effects, including cardiac toxicity. It is a problem that researchers reporting in the December 2007 issue of the Journal of Clinical Investigation suggest they can eliminate.

"This is the first time ever, to the best of my knowledge, that somebody has taken a drug with side effects and rationally reengineered it to remove the side effects," lead author Dr Ariel Fernández (Rice University, Houston, TX) said in an interview. "If we can control side effects in this rational manner, as we have shown here, we can truly revolutionize the drug-discovery enterprise."

In an accompanying editorial, Dr George Demetri (Ludwig Center for Cancer Research at the Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA) applauds the work [2].

"Fernández et al present a novel approach using structure-based rational drug design and medicinal chemistry to reengineer imatinib in order to retain its anticancer activity, but importantly, without the risks of cardiotoxicity," he writes. "Reengineering a drug substance, or 'scaffold,' based on structural insights is an artful process in which technology and imaginative creativity combine."

Imatinib is a selective small-molecule tyrosine inhibitor. Demetri points out that it has become the "poster-child drug" of small-molecule molecular therapeutics. Although relatively selective, imatinib inhibits a number of different tyrosine kinases, including the ABL family, and has potent activity against mutated oncogenic forms of the receptor tyrosine kinase KIT and the platelet-derived growth factor receptor-alpha.

In their paper, the researchers note that targeting kinases is central to drug-based cancer therapy but remains a challenge because the drugs often lack specificity, which can cause toxic adverse effects.

Fernández and colleagues modified the chemical structure of imatinib by deleting its ABL-inhibitory activity. The anticancer activity of the reengineered agent, called WBZ-4, was instead preserved against gastrointestinal stromal tumors in both in vitro and in vivo models by inhibiting the KIT tyrosine kinase instead of JNK, and the desired safety was demonstrated with less cardiotoxicity.

Demetri explains that the team made some fundamental choices in this work. First, they chose to focus on retaining the KIT-inhibitory activity of imatinib as their primary aim, while diminishing the ABL-inhibitory activity of the reengineered compound. The reasoning for this was that the mutated version of KIT is a valid oncogenic target in GIST and in a subset of melanomas.

"Dialing out the ABL-inhibitory activity would, of course, make the newly reengineered agent less useful as a treatment for CMLs, but the hope of these investigators was to create a less cardiotoxic drug that could be used for the treatment of GIST and other KIT-dependent malignancies," he writes.

Dr Thomas Force (Thomas Jefferson University, Philadelphia, PA), who published the first findings last year implicating ABL inhibition in the risk for heart failure [3], said this latest paper is an important step in drug development.

"The reason we had set out to identify the basic mechanisms by which anticancer 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," Force said in a news release.

"Fernandez and coworkers, in this really remarkable piece of work, have proven that this is indeed possible," he said. "Their findings will hopefully encourage drug makers to pursue a similar approach of 'rational drug redesign' in the development of new anticancer agents, thereby retaining anticancer activity with limited toxicity."

Demetri notes that the first generation of kinase-inhibitory drugs, such as imatinib and sunitinib (Sutent, Pfizer), have already provided patients with life-saving therapeutic options and, with tools such as those described by researchers, the future certainly looks bright for constructing ever-better agents that can be combined safely and effectively to manage and eventually cure many forms of human cancer.

"The approach used here by Fernández et al holds great promise to allow more customized development of rationally designed therapeutic agents," Demetri adds.

During an interview, senior author Dr Gabriel Lopez-Berestein (University of Texas MD Anderson Cancer Center, Houston) said: "We have developed a new and rational way to design drugs that are more target-selective, leading to better activity and lower toxicity. This finding can be applied to a wide variety of diseases."