
Description | Belvarafenib(GDC5573,HM95573,RG6185)isaselectiveandorallybioavailablepan-RAFkinaseinhibitorwithIC50valuesof41nM,7nMand2nMforBRAFWT,BRAF(V600E)andCRAFkinases,respectively. | ||||||
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Targets |
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Invitro | Biochemicallyassayedforover120kinases,HM95573showsthehighselectivitytowardBRAFmutantandCRAFkinases.Thehalfmaximalinhibitionconcentrations(IC50)ofHM95573againstBRAFWT,BRAFV600EandCRAFkinasesare41nM,7nMand2nM,respectively.ThestronglyinhibitedkinasessubsequenttoRAFkinasesappeartobeCSF1R(44nM),DDR1(77nM)andDDR2(182nM).HM95573potentlyinhibitsthegrowthofmutantBRAFmelanomacelllinessuchasA375(IC50:57nM)andSK-MEL-28(69nM)andofmutantNRASmelanomacelllinessuchasSK-MEL-2(53nM)andSK-MEL-30(24nM).Inaddition,thephosphorylationsofMEKandERKdownstreamkinasesassociatedwithcellproliferationareeffectivelyinhibitedwithtreatmentofHM95573inmutantBRAFandmutantNRASmelanomacells.HM95573inhibitsthedownstreamsignalinginmelanomacellseveninthepresenceofHGFwhichisknowntomediateinnateresistancetoRAFinhibitors[1]. | ||||||
Invivo | HM95573showstheexcellentantitumoractivityinmousemodelsxenograftedwithbothofBRAFmutationcelllines(e.g.A375andSK-MEL-28)andNRASmutationcelllines(suchasSK-MEL-2andSK-MEL-30)[1]. |
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