TurnandFacetheStrange:§ANewViewonPhosphatasesMajaKöhn*CiteThis:ACSCent.Sci.2020,6,467−477ReadOnlineACCESSMetrics&MoreArticleRecommendationsABSTRACT:Phosphorylationasapost-translationalmodificationiscriticalforcellularhomeostasis.Kinasesandphosphatasesregulatephosphorylationlevelsbyaddingorremoving,respectively,aphosphategroupfromproteinsorotherbiomolecules.Imbalancesinphosphorylationlevelsareinvolvedinamultitudeofdiseases.Phosphatasesareoftenthoughtofastheblacksheep,thestrangers,ofphosphorylation-mediatedsignaltransduction,particularlywhenitcomestodrugdiscoveryanddevelopment.Thisisduetopastdifficultiestostudythemandunsuccessfulattemptstotargetthem;however,phosphataseshaveregainedstrongattentionandareactivelypursuednowinclinicaltrials.Bygivingexamplesforcurrenthottopicsinphosphatasebiologyandfornewapproachestotargetthem,itisillustratedherehowandwhyphosphatasesmadetheircomeback,andwhatisenvisionedtocomeinthefuture.■INTRODUCTIONPhosphatasesremovephosphategroupsfrombiomoleculesandaretheimportantcounterplayersofkinases,togethergoverningthephysiologicalphosphorylationstatebalance.Imbalanceoftheregulationofphosphorylationanddephosphorylationcancontributetothedevelopmentandprogressionofamyriadofdiseases,placingkinasesandphosphatasesinimportantpositionsfordrugtargeting.Whilekinaseshavebeensuccessfullytargetednumeroustimestotreatdiseases,especiallycancer,1thisisnotthecaseforphosphatases.2Onereasonisthattheinitialfocusforphosphatasesinhibitordevelopmentwasonactivesiteinhibitors.Activesiteinhibitorsforphosphatasesgenerallysufferfromlimitedselectivityandbioavailability.Thisisduetothestrongactivesiteconservationandthepreferenceoftheactivesitefornegativechargesthatareoftenrequiredtoensuretightbinding.2Incontrast,targetingoftheATP-bindingpocketinkinaseshasbeenhighlysuccessfulandresultedinseveralapproveddrugs.1Reasonsarethatnegativechargesarenotrequiredforbinding,whichimprovestheirbioavailability,andthatselectivitycanbeachievedtoanextentthatissufficientforthetreatmentofcance...
