中文名称PROTACKRASG12CDegrader-LC-2中文同义词(2S,4R)-1-((S)-2-(3-(3-((S)-2-(((7-(8-氯萘-1-基)-4-((S)-3-(氰基甲基)-4-(2-氟丙烯酰基)哌嗪-1-基)-5,6,7,8-四氢吡啶并[3,4-D]嘧啶-2-基)氧基)甲基)吡咯烷-1-基)丙氧基)丙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺;LC2|||PROTACKRASG12CDEGRADER-LC-2|||LC2英文名称PROTACKRASG12CDegrader-LC-2英文同义词PROTACKRASG12CDegrader-LC-2;LC-2;(2S,4R)-1-((S)-2-(3-(3-((S)-2-(((7-(8-Chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)propoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(3-(3-((S)-2-(((7-(8-Chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)propoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-mCAS号2502156-03-6分子式C59H71ClFN11O7S分子量1132.78EINECS号相关类别Mol文件MolFile结构式PROTACKRASG12CDegrader-LC-2性质密度1.297±0.06g/cm3(PredChemicalbookicted)储存条件Storeat-20°C溶解度DMSO:50mg/mL(44.14mM;超声加热并加热至80°C)形态固体酸度系数(pKa)14.07±0.40(Predicted)颜色米白色至棕色PROTACKRASG12CDegrader-LC-2用途与合成方法生物活性LC-2是首创的内源性KRASG12C的PROTAC降解剂,DC50在0.25和0.76μM之间。LC-2是一种PROTAC,与MRTX849共价结合KRASG12C并招募E3连接酶VHL,诱导KRASG12C快速持续降解,导致纯合和杂合子KRASG12C细胞系MAPK信号的抑制。靶点KRAS(G12C)0.25-0.76μM(DC50)VHL体外研究LC-2inducesdegradationofendogenousKRASG12CinmultipleKRASmutantcancercell(NCI-H2030,MIAPaCa-2,SW1573,NCI-H23andNCI-H358cells)withDC50sbetween0.25and0.76μM.LC-2-inducedKRASG12CdegradationoccursviaabonafidePROTACmechanism.MIAPaCa-2,NCI-H23,andSW1573cellsaretreatedwith2.5μMofLC-2for6,24,48,and72h.Inallthreecelllines,maximalKRASdegradationoccurredwithin24handwassustainedupto72h.LC-2-induced(2.5μM;6-24hours)KRASG12CdegradationmodulatesErksignalinginhomozygousandheterozygousKRASmutantcelllines.WesternBlotAnalysisCellLine:MIAPaCa-2cellsandNCI-H23cellsConcentration:2.5μMIncubationTime:6-24hoursResult:InhibitionanddegradationofKRASG12CdecreasespErksignalingat6and24hinhomozygousMIAPaCa-2cells |