Tankyrase1andtankyrase2aremembersofPARPfamily.TheycanuseNAD+assubstratestotransferADP-ribosepolymersontotargetproteins.ThetankyrasesbindandPARSylateaxinproteinswhicharethenegativeregulatorofWntpathway.Thustankyrasesarepromisingtargetsfortreatmentforadenomatouspolyposiscoli.Tankyraseinhibitor49isanoptimizationoftheprevioushitcompoundinhibitor8withimprovedpotencyandselectivity.Ithasexcellenteffectsinbothtankyraseassayandcellularassay(totalβ-catenindegradationassayinSW480cells)withIC50valuesof0.1nMand1.9nM,respectively.Inaddition,itisfoundtobeadualbinderwithboththenicotinamidepocketandtheinducedpocketoftheenzymes.Intheinvivostudiesinrodents,tankyraseinhibitor49isfoundtopotentlyinhibitTNKS2autoparsylationwithIC50=7.6nM.Italsocausesst
ABIlizationandaccumulationofaxinproteininSW480cellswithEC50=4nM.InDLD-1cellswithtruncatedAPC,theinhibitorinhibitstheSTFreportertranscriptionwithIC50=0.3nM,suggestingitsdownstreaminhibitoryactivityonWnt-associatedtranscription.