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news.Ambit Biosciences has published evaluations and potential new uses for various compounds including Novartis' Gleevec, AstraZeneca's Iressa, OSI Pharmaceuticals and Genentech's Tarceva, plus a number of experimental kinase inhibitors.
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The study data was obtained by applying Ambit’s novel kinase profiling technology to evaluate the specificity of 20 compounds and reveal potential new uses for some.
“Kinases play key roles in cancer, inflammation, diabetes and other diseases, making kinase inhibitors one of the most important drug classes,” explained Dr David Lockhart, Ambit’s president and chief scientific officer.
“Ambit’s novel technology allows us to quickly and efficiently test kinase inhibitors against nearly 200 kinases at once, revealing how well the compounds bind to their intended targets and exposing ‘off-target’ binding that may be responsible for side-effects or that might even reveal unforeseen opportunities to use the compounds to treat other diseases,” Lockhart continued.
One finding was that Gleevec, indicated for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors, was found to bind tightly to a kinase known as LCK, a key regulator of T-cell maturation and activation, indicating that Gleevec or close derivatives may be clinically useful as an immunosuppressant.
Meanwhile, BIRB-796, which was until recently in clinical trials with Boehringer Ingelheim in various inflammatory and autoimmune diseases, was found to bind tightly to a Gleevec-resistant form of the kinase ABL (T3151), the toughest of the Gleevec-resistant mutations, indicating that BIRB-796 or close derivatives may have the potential to treat Gleevec-resistant cancers.
The study also questioned the notion that differences in patient response to AstraZeneca’s Iressa are linked to certain mutations in the kinase known as EGFR.
Ambit found that Iressa and other compounds that target EGFR such as Tarceva, Novartis’ PKI-166, GlaxoSmithKline’s GW-2016 and Baxter and Sugen’s SU-11464, all bind tightly to wild-type (normal) EGFR. Each of the nine mutant forms of EGFR tested with similar affinity, indicating that these mutations do not enhance the ability of the compounds to bind EGFR and that there must be other causes for the increased response in certain patient groups.
Compounds such as Gleevec, GW-2016 and Novartis and Schering AG’s Vatalanib (PTK-787) bind few kinases other than their primary targets, while compounds such as Pfizer’s SU11248, Celgene’s SP600125, Wyeth’s EKB-569 and Astrazeneca’s ZD-6474 bind a host of other kinases, in some cases with a strength similar to that with which they bind their primary targets.