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1、Small-moleculeligandsbindtoadistinctpocketinRasandinhibitSOS-mediatednucleotideexchangeactivityTillMaurera,1,LindsayS.Garrentonb,1,AngelaOha,KeithPittsc,DanielJ.Andersonb,NicholasJ.Skeltond,BenjaminP.Fauberd,BorlanPana,ShivaMalekc,DavidStokoeb,MaryJ.C.Ludlamb,KristaK.Bowmana,JianshengWue,An
2、thonyM.Giannettic,MelissaA.Starovasnika,IraMellmanb,PeterK.Jacksonb,JoachimRudolphd,WeiruWanga,2,andGuoweiFangb,2aStructuralBiology,bResearchOncology,cBiochemicalandCellularPharmacology,dDiscoveryChemistry,andeProteinChemistry,Genentech,Inc.,OneDNAWay,SouthSanFrancisco,CA94080Editedby*Sung-
3、HouKim,UniversityofCalifornia,Berkeley,CA,andapprovedFebruary2,2012(receivedforreviewOctober6,2011)TheRasgeneisfrequentlymutatedincancer,andmutantRasreportedtobindtoRas(3–7),buttheirmechanismsofactionanddrivestumorigenesis.AlthoughRasisacentraloncogene,smallthestructuralbasistoachieveRasinh
4、ibitionremainelusive.moleculesthatbindtoRasinawell-definedmannerandexertFragment-basedleaddiscovery(FBLD)hasprovidedastart-inhibitoryeffectshavenotbeenuncoveredtodate.ThroughaningpointtodevelopanumberofchemicalentitiesfortargetsNMR-basedfragmentscreen,weidentifiedagroupofsmallmole-previousl
5、yconsidered“undruggable,”notablyBcl2(reviewedinculesthatallbindtoacommonsiteonRas.High-resolutioncocrys-ref.8).Thisapproachhasbenefitedinparticularfromtheuseoftalstructuresdelineatedauniqueligand-bindingpocketontheNMRandsurfaceplasmonresonanceforultrasensitivedetectionRasproteinthatisadjace
6、nttotheswitchI/IIregionsandcanbeofinteractionsbetweenligandandprotein,evenatmillimolarexpandeduponcompoundbinding.Structureanalysispredictsaffinities.Asidefromtheidentificationofligandsforaknownthatcompound-bindinginterfereswiththeRas/SOSinteractions.bindingsite,afragment-basedscreencanalso
7、revealuniquebind-Indeed,selectedcompoundsinhibitSOS-mediatednucleotideingsitesinproteins.CentraltothisdiscoveryprocessistheabilityexchangeandpreventRasactivationbyblockingtheformationtoobtainhigh-resolutionstructuresoftheligand-proteincom-ofintermediates
