| Description | TAS6417isanovelEGFRinhibitorthattargetsEGFRexon20insertionmutationswhilesparingwild-type(WT)EGFR.IC50valuesrangesfrom1.1±0.1to8.0±1.1nmol/L. | |||||||||||
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| Invitro | Ofthe255kinasestested,TAS6417inhibits25kinasesotherthanEGFRwithIC50valueslessthan1,000nmol/L,whichwas100timeshigherthanitsIC50valueagainstWTEGFR.ItinhibitsonlysixkinasescontainingTXK,BMX,HER4,TEC,BTK,andJAK3,withIC50valueslessthan10timesthatagainstWTEGFR.TAS6417inhibitsproliferationofBa/F3cellsdrivenbyvariousEGFRexon20insertionmutations,withIC50valuesrangingfrom5.05±1.33nmol/Lto150±53nmol/L.Italsosuppressesthegrowthofcellsexpressingexon20insertionmutationsoftheEGFRgene,withaGI50valueof86.5±28.5nmol/LforLXF2478Lcellsand45.4±2.6nmol/LforNCI-H1975EGFRD770_N771insSVDcells.TAS6417hasnoeffectonEGFR-independentproliferationinNCI-H23orNCI-H460cells[1]. | |||||||||||
| Invivo | TAS6417causespersistenttumorregressioninvivoinEGFRexon20insertion-driventumormodels.ThetumorregressionoccurrsquicklyafterTAS6417treatmentandpersistsduringthetreatmentperiod.PharmacokineticanalysisrevealsthattheplasmaconcentrationofTAS6417,admiNISTeredat50and100mg/kgtomice,decreasesrapidlyinthefirst4hours.Incontrast,althoughtheeffectivedosesintheratmodelexhibitlowermaximumplasmaconcentration(Cmax)valuesthanthoseinthemousemodel,theplasmaconcentrationstendtobemorepersistent,lastingupto8hours.TAS6417inhibitsmutantEGFRintumorsbutnotWTEGFRinskintissues.Itprolongssurvivalofanimalsbearinglungcancer[1]. |
