A more selective version of Novartis’ blockbuster anticancer Glivec (imatinib, Gleevec) that could avoid the drug’s association with heart failure has shown promise in preclinical studies. The downside is that the re-engineered imatinib would have no efficacy against the core leukaemia indications approved for the drug.

The study published in the 3 December issue of the Journal of Clinical Investigation does confirm the suggestion that the increased risk of cardiotoxicity seen with imatinib in chronic myeloid leukaemia (CML) is due to its mechanism of action in inhibiting the tyrosine kinase protein Bcr-Abl. This protein is implicated in Philadelphia chromosome-positive CML and another approved Glivec indication, Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL).

The other main indication for Glivec is in gastrointestinal stromal tumour (GIST), a rare form of stomach cancer with an incidence of around 15-20 new cases per million population in the US each year. The target receptor for GIST is another tyrosine kinase protein, C-Kit, and the re-engineered version of imatinib developed by US researchers at Rice University and the University of Texas M D Anderson Cancer Center is designed to home in on C-Kit without inhibiting the function of Bcr-Abl.

The result is a drug with a narrower therapeutic spectrum but one that may be free of cardiotoxic side-effects. In computer models, in vitro assays and experimental animals, the redesigned imatinib – coded as WBZ-4 – was shown to be just as effective as the original drug at inhibiting C-Kit and halting the growth of GIST cancers, while in animal tests the risk of cardiotoxicity was significantly reduced with WBZ-4 versus imatinib, the researchers reported.

Dr Thomas Force, professor of medicine at Thomas Jefferson University and lead author of the study published last July in Nature Medicine that raised concerns about imatinib and heart failure as well as positing the link with Bcr-Abl inhibition, welcomed the findings by Ariel Fernandez, professor of bioengineering at Rice University, and colleagues working under the rubric of the Rice-M D Anderson Partnership for Cancer Drug Discovery.

“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 would potentially steer drug development away from targets and pathways that would lead to toxicity but would leave tumour cell killing intact,” Force commented.

“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’ (and drug design) in the development of new anticancer agents, thereby retaining anticancer activity with limited toxicity.”

Rational design strategy
WBZ-4 was designed at Rice University, based on a new “bottom up” rational strategy that Fernandez, who developed the approach, says is “broadly applicable to drugs other than imatinib. The new version is identical to imatinib, except for the addition of four atoms to form a ‘molecular bandage’ that is designed to keep water molecules away from a key reaction site on C-Kit not present in the Bcr-Abl kinase.

Through careful positioning of this ‘bandage’, the researchers managed to ensure that WBZ-4 would not inhibit the effect of Bcr-Abl and hence narrowed its specificity to C-Kit. They also found that WBZ-4 inhibited another, similar tyrosine kinase, JNK, whose suppression has been shown in previous studies to protect against imatinib-induced cardiotoxicity.

While re-engineering imatinib in this way effectively strikes out the drug’s leukaemia indications, the researchers said the C-Kit protein was “a suspect” in cancers other than GIST.

To date, no clinical trials have been scheduled with WBZ-4, which was incorporated into liposomal nanoparticles to facilitate drug formulation and delivery for the preclinical tests.