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

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Duveau DY, Hu X, Walsh MJ, Shukla S, Skoumbourdis AP, Boxer MB, Ambudkar SV, Shen M, Thomas CJ

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

Bioorg Med Chem Lett. 2013 Feb 1;23(3):682-6. doi: 10.1016/j.bmcl.2012.11.111. Epub 2012 Dec 10.

PubMed ID

23273517 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Nilotinib	Tyrosine-protein kinase ABL1	Kd (nM)	3.6	N/A	N/A	Details