Kinasescatalysethetransferoftheγ‑phosphategroupofATPontoatargetsubstrate.Asequenceofsuchphos‑phorylationeventsregulatesnumerouscellularactivities,suchasproliferation,survival,apoptosis,metabolism,transcriptionanddifferentiation.Theseprocessesoftencontributetohomeostasis,anddysregulatedactivityofkinasesunderliesmalignant,inflammatoryandneuro‑degenerativedisorders.Aberrantkinasefunctionshavealsobeenlinkedtocardiovasculardiseasesandcompli‑cationsindiabetes.Thus,kinasesarethefocusofintensebasicanddrugdiscoveryresearch,andtheUSFoodandDrugAdministration(FDA)hassofarapprovedmorethan30small‑moleculekinaseinhibitors.Exceptfortofacitinibandnintedanib,whichareapprovedforthetreatmentofrheumatoidarthritisandidiopathicpulmo‑naryfibrosis,respectively,allclinicalkinaseinhibitorsareusedforcancertherapy1.Kinaseinhibitorsarecategorizedonthebasisoftheirbindingmodes.TypeIinhibitorstargettheATPpocketofthekinaseintheactivestate,whereastypeIIinhibitorsbindwithintheATPpocketofakinaseintheinactivestate.TypeIIIinhibitorsareallostericinhibi‑torsthatbindoutsidetheATPpocketinamannerthatdoesnotcompetewithATP.TypeIVinhibitorsinterferewiththesurfacesthatarenecessaryforprotein–proteininteractions2.AstypeIIIandtypeIVinhibitorstargetpocketsthatareuniquetoeachkinase,thesecompoundsareusuallyselectivewithinthekinome.BecauseofthehighlyconservedATP‑bindingsitesacrosskinases,selectivityoftypeIandtypeIIinhibitorshaspreviouslybeenconsideredamajorchallenge.However,thisviewhassubstantiallychangedowingtoadvancesinstruc‑turalbiology,large‑scalekinomeprofilingandadetailedunderstandingofthestructure–activityrelationshipsforthesecompounds.Assuch,highlyselectivekinaseinhibitorsthattargettheATPpocketarenowavailable.However,themajorityofclinicallyusedkinaseinhibitorstargetnumerouskinasessimultaneously.Importantly,advancedtechnologyplatformshavebeendevelopedtoprofilekinaseinhibitorsacrossthekinome,andtheirkinaseselectivityisextensivelycoveredintheliterature3–6.Inadditiontokinomeprofiling,invitroprofilin...
