| Description | Borussertibisacovalent-allostericinhibitorofproteinkinaseAktwithanIC50of0.8nMandaKiof2.2nMforWTAkt. | ||
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| Invitro | Borussertibexhibitsexcellentcellularactivityinthenanomolarrange.TheEC50values(cellviABIlityassay)ofborussertibinAN3CA,T47D,ZR-75-1,MCF-7,BT-474andKU-19-19cellsare191nM,48nM,5nM,277nM,373nMand7770nM,respectively[1].Borussertibspecificallybindstotwonon-catalyticcysteinesinAKTatpositions296and310bydecoratingallostericligandswithelectrophilicwarheadsatsuitablepositions,thusenablingtheirreversIBLestabilizationoftheinactiveconformation.BorussertibpotentlyinhibitsproliferationofPI3K/PTEN-mutatedcelllines[2]. | ||
| Invivo | Borussertibrevealsagoodpharmacokineticprofilewithreasonablemicrosomalstabilityinhumanandmurinemicrosomes[1].PKstudiesarecarriedoutinmice(2mg/kgintravenous;20mg/kgoralgavage;20mg/kg,intraperitoneal),Despitearatherloworalbioavailability(<5%),reachingonlyamaximumplasmaconcentrationof78ng/mL(0.13µM),ThereisasignificantlyhigherbioavailabilityuponintraperitonealadmiNISTration(39.6%),withmaximumplasmalevelsof683ng/mL(1.14µM)[2]. |
