Synthesis and biological evaluation of analogues of the kinase inhibitor nilotinib as Abl and Kit inhibitors

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Abstract

The importance of the trifluoromethyl group in the polypharmacological profile of nilotinib was investigated. Molecular editing of nilotinib led to the design, synthesis and biological evaluation of analogues where the trifluoromethyl group was replaced by a proton, fluorine and a methyl group. While these analogues were less active than nilotinib toward Abl, their activity toward Kit was comparable, with the monofluorinated analogue being the most active. Docking of nilotinib and of analogues 2a–c to the binding pocket of Abl and of Kit showed that the lack of shape complementarity in Kit is compensated by the stabilizing effect from its juxtamembrane region.

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Acknowledgments

We thank Jim Bougie, Thomas Daniel and William Leister for compound purification, as well as Paul Shinn, Danielle VanLeer and Christopher LeClair for assistance with compound management. This research was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research Grant U54HG005033 and the Intramural Research Program of the National Human Genome Research Institute at the National Institutes of Health. S. Shukla and S.V. Ambudkar were

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