EMD638683isahighlyselectiveSGK1inhibitorwithIC₅₀of3μM.

IC50:3μM(SGK1)^[1]

EMD638683isaSGK1inhibitor.EMD638683inhibitstheNDRG1(N-Mycdownstream-regulatedgene1)phosphorylation,aneffectrequiring3.35±0.32μMEMD638683inthecellculturemediumforhalfmaximaleffect(IC₅₀).EMD638683hasalsoaninhibitoryeffectoncAMP-dependentproteinkinase(PKA),mitogen-andstress-activatedproteinkinase1(MSK1),proteinkinaseC-relatedkinase2(PKR2),andtheSGKisoformsSGK2andSGK3^[1].Inboth,controlandEMD638683(50µM)-treatedCaCo-2cells,rADIationsignificantlyincreasesthepercentageofCaCo-2cellsundergoinglateapoptosis.EMD638683treatmentalonetendstoenhancethepercentageofapoptoticCaCo-2cells.FollowingradiationthepercentageofapoptoticEMD638683-treatedCaCo-2cellsissignificantlyhigherthanthepercentageofapoptoticcontrolcells.Thus,EMD638683treatmentsignificantlyaugmentstheapoptosisfollowingradiation^[2].

ThecolonissignificantlylongerandthecolonweightsignificantlylowerinEMD638683-treatedmicethaninplacebo-treatedmice,afindingpointingtoaninfluenceofEMD638683ontumorgrowthfollowingchemicalcarcinogenesis.Inaddition,thestomachweightissignificantlylowerintheEMDtreatedgroup.Mostimportantly,thenumberofdevelopingtumorsfollowingcarcinogenictreatmentissignificantlybluntedbyEMD638683treatment^[2].EMD638683(20mg/kg,intragastrically)preventsprogressionofmonocrotaline(MCT)-inducedpulmonaryvascularremodelinginrats.HemodynamiccharacteristicsshowthatEMD638683treatmentattenuatesrightventricularsystolicpressure(RVSP)(15.8±2.5vs.28.2±3.1mmHg;P<0.05; n="6)" and="" right="" ventricular="" hypertrophy="" index="" (rvhi)="" (0.27±0.02="" vs.=""><0.05; n="6)" compare="" to="" vehicle-dosed="">^[3].

• [1].AckermannTF,etal.EMD638683,anovelSGKinhibitorwithantihypertensivepotency.CellPhysiolBiochem.2011;28(1):137-46.

  [2].TowhidST,etal.InhibitionofcolonictumorgrowthbytheselectiveSGKinhibitorEMD638683.CellPhysiolBiochem.2013;32(4):838-48.

  [3].XiX,etal.Serum-glucocorticoidregulatedkinase1regulatesmacrophagerecruitmentandactivationcontributingtomonocrotaline-inducedpulmonaryarterialhypertension.CardiovascToxicol.2014Dec;14(4):368-78.

  [4].ZhouH,etal.Inhibitionofserum-andglucocorticoid-inducIBLekinase1enhancesTLR-mediatedinflammationandpromotesendotoxin-drivenorganfailure.FASEBJ.2015Sep;29(9):3737-49.

EMD638683isdissolvedinDMSOandstored,andthendilutedwithappropriatemediabeforeuse^[2].

Coloncarcinoma(CaCo-2)cellsaregrownincompleteDMEMmediumcontaining10%fetalcalfserum,1%sodiumpyruvate,1%penicillin-streptomycinand1%non-essentialaminoacidsunderstandardcultureconditions(37°C,5%CO₂).10⁵cellsareseededin6wellplatesandculturedwithfreshculturemediumfor24h,afterwhichEMD638683(50µM)isappliedfor24hours.Forcomparison,thecellsaretreatedwiththesolvent(0.2μLDMSO)andonesolventcontrolisanalysedwitheachsetofexperiments.Thecellsaresubsequentlyexposedto3.18minradiation(3Gray).Afterfurtherincubationfor72hinthepresenceorabsenceofEMD638683(50µM)thecellsareanalyzedutilizingflowcytometry^[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

EMD638683issynthesizedbyHaoyuan(Shanghai,China)anddissolvedin1%DMSO^[3].

RatandMice^[3]
PAHisinducedin2-month-oldmaleSprague-DawleyratsbyadministeringasinglesubcutaneousinjectionofMCT(60mg/kg,n=12).Ratsinthecontrolgrouparegiventhevehiclesaline(0.5mL,subcutaneously,n=12).SixratsineachgrouparegivenEMD638683(20mg/kg)intragastricallyoncedailystarting2dayspriortoMCTtreatment.Ratsareanesthetizedwithsodiumpentobarbital(50mg/kgintraperitoneally).Rightventricularsystolicpressure(RVSP),rightventricularhypertrophy,andpulmonaryvascularremodelingareevaluated21daysafterMCTinjection.Attheageof10-12weeks,maleSGK1^-/-miceandtheirwild-type(WT)littermatesaregivenMCTindosesof60mg/100gbodyweightonceaweekfor8consecutiveweeksbysubcutaneousinjectiontoinducePAH.Thereareeightmicepergroup.Miceareanesthetizedwithsodiumpentobarbital(50mg/kgintraperitoneally)onday8afterthelastMCTadministration.ThenRVSP,rightventricularhypertrophy,andpulmonaryvascularremodelingareevaluated.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

• [1].AckermannTF,etal.EMD638683,anovelSGKinhibitorwithantihypertensivepotency.CellPhysiolBiochem.2011;28(1):137-46.

  [2].TowhidST,etal.InhibitionofcolonictumorgrowthbytheselectiveSGKinhibitorEMD638683.CellPhysiolBiochem.2013;32(4):838-48.

  [3].XiX,etal.Serum-glucocorticoidregulatedkinase1regulatesmacrophagerecruitmentandactivationcontributingtomonocrotaline-inducedpulmonaryarterialhypertension.CardiovascToxicol.2014Dec;14(4):368-78.

  [4].ZhouH,etal.Inhibitionofserum-andglucocorticoid-induciblekinase1enhancesTLR-mediatedinflammationandpromotesendotoxin-drivenorganfailure.FASEBJ.2015Sep;29(9):3737-49.

364.34

C₁₈H₁₈F₂N₂O₄

1181770-72-8

RoomtemperatureincontinentalUS;mayvaryelsewhere

DMSO

EMD638683isfixedin4%formaldehyde^[4].

*"<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">

• [1].AckermannTF,etal.EMD638683,anovelSGKinhibitorwithantihypertensivepotency.CellPhysiolBiochem.2011;28(1):137-46.

  [2].TowhidST,etal.InhibitionofcolonictumorgrowthbytheselectiveSGKinhibitorEMD638683.CellPhysiolBiochem.2013;32(4):838-48.

  [3].XiX,etal.Serum-glucocorticoidregulatedkinase1regulatesmacrophagerecruitmentandactivationcontributingtomonocrotaline-inducedpulmonaryarterialhypertension.CardiovascToxicol.2014Dec;14(4):368-78.

  [4].ZhouH,etal.Inhibitionofserum-andglucocorticoid-induciblekinase1enhancesTLR-mediatedinflammationandpromotesendotoxin-drivenorganfailure.FASEBJ.2015Sep;29(9):3737-49.