Kinaseshavebeenintensivelyinvestigatedasdrugtargetsforthepast30years,with38kinaseinhibitorsapprovedtodate1.Thesedrugsarepredominantlymultitargetedreceptortyrosinekinase(RTK)inhibitorsapprovedforthetreatmentofcancer2,suchasimatinib.Thereare518kinasesencodedinthehumangenome,andtheseenzymesphosphorylateuptoone-thirdoftheproteome3,4.Virtuallyeverysignaltransductionprocessoccursviaaphospho-transfercascade,indicatingthatkinasesprovidemultiplenodesfortherapeuticinterventioninmanyaberrantlyreg-ulatedbiologicalprocesses5.Indeed,inadditiontocancer,deregulationofkinasefunctionhasbeendemonstratedtoplayanimportantroleinimmunological,inflammatory,degenerative,metabolic,cardiovascularandinfectiousdiseases6,7.Theestablisheddruggabilityandtheclinicalsafetyprofileofapprovedkinaseinhibitorsmakekinasesattractivetargets.However,themajorityofkinaseshavebeenhistoricallyunderstudied,indicatingthatthefieldofkinaseinhibitordiscoveryisstillimmature8–10.In2013,CohenandAlessi2outlinedsomeofthemostimportantchallengesthatremainedinkinaseinhibitordrugdiscovery,whichwerelimitingthefullpotentialofkinasesasdrugtargetsinoncologyandbeyond.Thislistincludedvalidatingnovelkinasetargets,utilizingkinaseinhibitorsinnon-oncologytherapeuticareas,overcom-ingdrugresistance,obtainingtargetselectivitytoreduceoff-target-mediatedtoxicityanddevelopingefficientcompoundscreeningandprofilingtechnologies.Overthecourseofthepast5years,immenseprogresshasbeenmadetowardsthesegoals,andthefieldofkinaseinhibitordiscoveryhasexpandedrapidlyinoncologyinadditiontoforgingintodifferentdiseaseareas,includingauto-immuneandinflammatorydiseaseaswellasdegenerativedisorders(FIG.1).Technologiesforassessingtheselectivityofkinaseinhibitorshavealsobecomeincreasinglysophisticated.Inparticular,thedevelopmentoftechniquesthatmeasureinhibitorprofilesinaphysiologicalenvironmentisanimportantmilestone.Suchtechniquesincludetheuseofamultitargetedkinaseprobeforuseincellcom-petitionlabellingorfluorescenceexperiments11andthermalproteomeprofiling(TPP)12....
