Hotline:400-820-3792Inhibitors ? ScreeningLibraries ? Proteinswww.MedChemEMCB-294Cat.No.:HY-176785S分子式: C??H??D?F?N?O?分子量: 635.65作用靶點: Ras;Apoptosis;p38MAPK;Caspase;TNFReceptor作用通路: GPCR/GProtein;MAPK/ERKPathway;Apoptosis儲存方式: PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性MCB-294是一種雙態(tài)泛KRAS抑制劑，對KRAS的選擇性高于NRAS和HRAS。MCB-294能夠結(jié)合活性(GTP結(jié)合)和非活性(GDP結(jié)合)形式的KRAS，其Kd值約為1pM和10nM。MCB-294廣泛抑制表達G12D、G12C、G12V、G12S、G13D和野生型KRAS的hTERT-HPNE細胞的生長，IC50值約700nM。MCB-294在KRAS突變腫瘤中誘導不可逆的凋亡(apoptosis)。MCB-294有效抑制KRASG12C耐藥癌細胞，重塑腫瘤免疫微環(huán)境。MCB-294可用于胰腺癌、結(jié)直腸癌和肺癌的研究[1]。IC50&TargetKRasG12CKRasG12CKRasG12CKRasG12DKRasG12DKRasG12DKRasG12VKRasG12VKRasG12VKRASG13DKRASG13DK-RasWTK-RasWTCaspase3體外研究MCB-294inhibitsthebindingofSOScattoKRASproteinsanddisruptedRAF-RBDpeptidebindingtoactiveKRASwithIC50valuesapproximatelyrangingfrom1to70nMandfrom20to150nM[1].MCB-294(1nM-100μM,5days)showssignificantanti-proliferativeeffectsonKRAS-dependentcancercellsthatrelyonKRAS(asPC-1(G12D),H358(G12C),LS180(G12V),HCT116(G13D),etc.)forgrowthandsurvival(24of30celllinestestedwithameanIC50ofaround125nM)whilesparingnormalcells(hTERT-HPNE,NCM460)(IC50>10μM)[1].MCB-294(0-100nM,0-72h)causesadose-dependentreductioninp-ERKlevels,persistentlyinhibitscomponentsoftheMAPKsignalingpathway(p-ERK,DUSP6,andcyclinD1)andinducesapoptosismarkers(CC3andcPARP)inAsPC-1andH358tumorsinalltestedKRAS-dependentcancercellsincludingMIAPaCa-2cellsexpressingKRASG12C,KRASG12C/Y96C,andKRASG12C/H95D[1].1/3 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEMCB-294downregulatespro-survivalgenes(BIRC5,MCL1,andBCL2L1),upregulatespro-apoptoticgenes(BBC3,BCL2L11,andBMF)anddecreasesKRAS-regulatedgenessuchasCCND1,DUSP6,ETV4,SPRY2,andPHLDA1[1].MCB-294significantlyupregulatestheinterferon-alpharesponsepathwayinCD45+immunecellsisolatedfromCT26tumorsandincreasestheabundanceofeffectorCD8+Tcells[1].WesternBlotAnalysis[1]CellLine:AsPC-1andH358cellsConcentration:0,10,30and100nMIncubationTime:0,3,6,12,24hResult:Inducedapoptosismarkers(CC3andcPARP)asearlyas6hpost-treatment,witheffectssustainedfor24hinKRAS-dependentcancercells.PreferentiallytrapedKRASinaninactivestate.WesternBlotAnalysis[1]CellLine:MIAPaCa-2(G12C),MIAPaCa-2(G12C/Y96C)andMIAPaCa-2(G12C/H95D)Concentration:30nMIncubationTime:0,1,3,6,12,24,36,48,72hResult:Inhibitedp-ERKlevels,inducedcelldeathandretainedtheirpotencyoveratleast36h.體內(nèi)研究MCB-36(10mg/kg,i.p.,singledose)achievesrapidsystemicexposure,reachingpeakplasmaconcentrationat0.5hpost-dosingwithaplasmaeliminationhalf-life(t1/2)of1.1h[1].MCB-294(30mg/kg,i.p.,twicedailyfor1-16days)effectivelysuppressesKRASG12Cinhibitor-resistantcancercellsandremodelthetumorimmunemicroenvironmentinmice[1].AnimalModel:AsPC-1/H358inducedxenograftmodelestablishedinsix-toeight-week-oldmaleBALB/cnudemice[1]Dosage:30mg/kgAdministration:Intraperitonealadministration(i.p.),twicedaily,for1or7daysResult:Observedp-ERKlevelsaccompaniedbyreducedplasmadrugconcentrationat6hpost-treatmentunderthe1-daydosingregimen,sustainedp-ERKsuppressionwasachievedwithcontinuous7-daydosing.AnimalModel:Patient-derivedxenograft(PDX)modelinducedbypancreaticductaladenocarcinomaharboringaKRASG12Dmutation(PDXA01),colorectalcarcinomaharboringaKRASG12Cmutation(PDXA02),andlungadenocarcinomaharboringaKRASG12V2/3 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemEmutation(PDXA03)establishedinfour-tofive-week-oldmaleBALB/cmice[1]Dosage:30mg/kgAdministration:Intraperitonealadministration(i.p.),twicedaily,for16daysResult:Inhibitedtumorgrowthandmaintainedtheinhibitoryeffectevenafterdiscontinuationofthemedication.Decreasedp-ERKandKi67levelsandincreasedcaspase3activity.Noabnormalitiesintheheart,liver,spleen,lungs,orkidneysandsignificantweightloss.AnimalModel:CT26inducedimmunoregulationmodelestablishedinsix-toeight-week-oldmaleBALB/cnudemice[1]Dosage:30mg/kgAdministration:Intraperitonealadministration(i.p.),twicedaily,for2daysResult:IncreasedtheabundanceofeffectorCD8+Tcells,IFN-γ,TNF-αandKi67.Enhancedtheefficacyofanti-PD-1therapy.REFERENCESFengJ,etal.Apan-KRASinhibitoranditsderiveddegraderelicitmultifacetedanti-tumorefficacyinKRAS-drivencancers.CancerCell.2025Jul