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Who Else Needs A Nilotinib ? by zhang qing
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Who Else Needs A Nilotinib ? |
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Health,Career,Blogs
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Hyperinsulinemia,12 postreceptor insulinresistance,13 and hypoadiponectemia14 play critical roles inthe development of dyslipidemia and atherosclerosis.Thus, our results not only explain the rapid and significantincrease in total and non-HDL cholesterol levels observedin this study , but also a possible mechanism ofthe development of peripheral artery occlusion ,which was recently described as an important Nilotinib of nilotinibtherapy.15In summary, for the first time we have clarified themechanism of impaired glucose metabolism in CML patients treated with nilotinib, which occurs via rapidly A major goal in the further development of kinase inhibitorsis to maintain a degree of specificity similar to that ofimatinib for Abl, thereby minimizing potential side effectsfrom off-target interactions. Thus, to identify potentialsecondary targets of these inhibitors, recent studies havefocused on chemical proteomics screens for drug-interactors. Briefly, the screens involve the generation ofmatrix-linked inhibitors that are used to pull down interactingproteins, which are then identified by mass spectrometryand validated by binding and activity studies.This approach has been pursued with imatinib and thesecond-generation inhibitors nilotinib, dasatinib, andbosutinib. In addition to the known targets of these inhibitors,additional kinase targets were identified. For imatinib,the screens also identified a surprising non-kinasetarget, the oxidoreductase NQO2, which also was shownto be a target of the second-generation inhibitor nilotinibbut not dasatinib or bosutinib . NQO2 is a cytosolic flavoprotein that carries out the 2-electron reduction of quinones using electron donorssuch as nicotinamide riboside . It is one of twoclosely related cellular quinone reductases and is thought to be involved in metabolicreduction and xenobiotic detoxification , althoughits precise physiological role remains uncertain .Interestingly, NQO2 is highly expressed in myeloid cells,the targets of imatinib in CML anticancer therapy, andRNAi knockdown of NQO2 in K562 cells, an immortalizedBcr-Abl-positive CML cell line, resulted in reducedproliferation rates . The phosphorylation of NQO2on a serine residue in K562 cells was observed , suggestingpotential regulation of the activity of the enzymeby phosphorylation. Imatinib and nilotinib inhibited the NQO2-mediatedreduction of the anticancer drug mitomycin C, with IC50values of 1 µM for imatinib and 1.8 µM for nilotinib .Another set of experiments demonstrated competitiveinhibition by imatinib of the NQO2-mediated reductionof menadione with a Ki of 39 nM, in linewith an IC50 value of 43 nM obtained by competitivebinding assay . These data, together with the observationthat imatinib levels reach ~1 µM in the serum ofpatients , imply that NQO2 inhibition occurs inimatinib-treated CML patients, raising the possibility thatNQO2 inhibition may contribute to the overall pharmacologicaleffects of these drugs.The exact mechanism by which NQO2 is inhibited byimatinib is unknown. Neither chemical proteomics studydetected turnover of imatinib by NQO2. One study proposedthat imatinib inhibits NQO2 activity via competitionwith the FAD cofactor for binding to the enzyme , while the other study reported competitive inhibitionwith respect to the substrate menadione .Here, we report studies undertaken to further understandthe structural basis for the molecular mechanism bywhich imatinib binds to and inhibits NQO2. Spectroscopicmeasurements confirmed the direct binding ofimatinib to NQO2, with concurrent changes in the flavinenvironment indicating that the FAD is not displaced byimatinib. We have solved the X-ray crystal structure ofNQO2 bound to imatinib to 1.75 ? resolution, whichshows that the drug is bound adjacent to the flavin isoalloxazinering. The X-ray structure further provides anexplanation for the binding specificity of NQO2 for imatiniband nilotinib, as well as for the effects of mutation ofthe reported phosphorylation sites on NQO2. To assess the inhibition of NQO2 by imatinib, a continuousspectrophotometric assay was used. Briefly, theNQO2-mediated reduction of menadione to menadiol iscoupled to the reduction of the dye 3--2,5-diphenyltetrazolium bromide bymenadiol, resulting in an increase in absorbance at 590nm. Nilotinib, dasatinib, and quercetin, a flavonoidNQO2 inhibitor that is also a non-specific kinase inhibitor, were included for comparison. As shown in Figure1B, imatinib inhibited NQO2 activity with an IC50value of 82 nM, approaching that observed for quercetin. These values are in the same range as thosedetermined previously . Nilotinib inhibitedNQO2 activity with an IC50 value of 381 nM, while dasatinibdid not inhibit NQO2 activity significantly at theconcentrations tested .
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