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1、REVIEWSFlyingundertheradar:thenewwaveofBCR–ABLinhibitorsAlfonsoQuintás-Cardama,HagopKantarjianandJorgeCortesAbstract
2、TheintroductionoftheBCR–ABLkinaseinhibitorimatinibmesylate(Gleevec;Novartis)revolutionizedthetreatmentofchronicmyeloidleukaemia(CML).However,mostpatientswithCML
3、receivingimatinibstillharbourmolecularresidualdiseaseandsomedevelopresistanceassociatedwithABLkinasedomainmutations.Thesecond-generationBCR–ABLinhibitorsnilotinib(Tasigna;Novartis)anddasatinib(Sprycel;Bristol–MyersSquibb)haveshownsignificantactivityafterimatinibfailureinclinic
4、altrials,butstillfacesimilarobstaclestoimatinib,includingnegligibleactivityagainstthefrequentBCR–ABLT315ImutationandmodesteffectsinadvancedphasesofCML.Variousmedicinalchemistryefforts,inpartaidedbystructuralstudiesoftheABLkinase–imatinibcomplexhaveresultedinthesynthesisofanewg
5、enerationofBCR–ABLinhibitors,someofwhichhaveshownencouragingpreliminaryactivityinclinicaltrials,includingagainstT315Imutants.Here,wediscusstheseemergingtherapies,whichhavethepotentialtoimprovetheoutcomeofpatientswithCML.Chronicmyeloidleukaemia(orchronicmyelogenoustargets(FIG.
6、1).Inthisrespect,theremarkableclinicalleukaemia;CML),whichischaracterizedbyincreasedsuccessoftheABLtyrosinekinaseinhibitor(TKI)4,5andunregulatedproliferationofpredominantlymyeloidimatinibmesylate(formerlySTI571orCGP5148B;cellsinthebonemarrow,occursmostcommonlyintheGleevec,Nova
7、rtis)inthetreatmentofpatientswithmiddle-agedandelderlyandaccountsfor15–20%ofallCMLhashighlightedthepotentialofmolecularlytar-casesofadultleukaemiainWesternpopulations.Thegetedanticancertherapies,andhassparkedtheexten-underlyingcauseofCMLisacharacteristicreciprocalsivedevelopme
8、ntanduseofsuchagentsincancersintranslocationbetweenchromosomes9and22,whichgeneral6,7.cytogeneticallyresultsinthePhiladelphiachromo-ProteinkinasessuchasABLhaveevolvedhighlysome(Ph)andmolecularlygivesrisetothechimericspecializedmechanismsfortransitioningbetweenBCR–ABL1gene1,2.In
9、CML,theproteinproductofthisactiveandinactivestates,andcrystal
