Abstract
Imatinib mesylate is the leading compound to treat chronic myeloid leukemia (CML) and other cancers, through its inhibition of Bcr-Abl tyrosine kinases. However, resistance to imatinib develops frequently, particularly in late-stage disease and has necessitated the development of new Bcr-Abl inhibitors. The synthesis of a new series of phenylaminopyrimidines, structurally related to imatinib, showed large interest since the introduction of nilotinib. Here, we compare the protein levels in K562 cells treated with either imatinib or with novel imatinib derivates. Our results revealed that among the 986 quantified proteins, 35 had significantly altered levels of expression by imatinib or its derivates. In a second series of experiments, we directly compared the proteomes of imatinib treated K562 cells with those K562 cells treated with any of the four imatinib derivates. More than 1029 protein were quantified, 80 of which had altered levels of expression. Both experiments pointed to changes in the expression of the ATP-dependent RNA helicase DDX3X and of two mitochondrial coiled-coil-helix-coiled-coil-helix domain-containing proteins.
Highlights
Chronic myeloid leukemia (CML) is a disorder of the hematopoietic stem cells
Ratios for identified proteins were calculated by comparing the XIC peak areas of all matched light peptides with those of the heavy peptides, and the results were verified by visual inspection of MS spectra with the Rover tool [27].The false discovery rate (FDR)
SILAC in combination with LC-MS/MS to assess possible changes in protein expression induced by these compounds in K562 cells
Summary
Chronic myeloid leukemia (CML) is a disorder of the hematopoietic stem cells. The disorder arises from a translocation between regions of chromosomes 9 and 22 [1]. Structural data revealed that imatinib interacts with an inactive conformation of the Abl kinase, which is destabilized by many imatinib resistance-conferring mutations [8] These mechanistic insights provide a rational basis for the development of second-generation inhibitors [9,10,11], such as the small molecule drugs bosutinib and dasatinib, which target the active kinase conformation and thereby overcome imatinib resistance in many Abl kinase variants [5,6,7]. We employed LC-MS/MS, along with differential SILAC labeling to assess alterations in protein levels in Bcr-Abl positive human K562 cells treated with imatinib and several. Our study tries to understand the influence of the drug structure in its selectivity of protein expression perturbation
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