Coexistence of filamentary and homogeneous resistive switching with memristive and meminductive memory effects in Al/MnO2/SS thin film metal–insulator–metal device

Abstract

The Aurora kinases play critical roles in the regulation of mitosisand are frequently overexpressed or amplified in human tumors. Selectiveinhibitors may provide a new therapy for the treatment of tumorswith Aurora kinase amplification. Herein we describe our lead optimizationefforts within a 7-azaindole-based series culminating in the identificationof GSK1070916 (17k). Key to the advancement of the series was theintroduction of a 2-aryl group containing a basic amine onto theazaindole leading to significantly improved cellular activity. Compound17k is a potent and selective ATP-competitive inhibitor of AuroraB and C with Ki* values of 0.38 卤 0.29 and 1.5 卤 0.4 nM, respectively,and is >250-fold selective over Aurora A. Biochemical characterizationrevealed that compound 17k has an extremely slow dissociation half-lifefrom Aurora B (>480 min), distinguishing it from clinical compounds1 and 2. In vitro treatment of A549 human lung cancer cells withcompound 17k results in a potent antiproliferative effect (EC50 =7 nM). Intraperitoneal administration of 17k in mice bearing humantumor xenografts leads to inhibition of histone H3 phosphorylationat serine 10 in human colon cancer (Colo205) and tumor regressionin human leukemia (HL-60). Compound 17k is being progressed to humanclinical trials. The Aurora kinases play critical roles in the regulationof mitosis and are frequently overexpressed or amplified in humantumors. Selective inhibitors may provide a new therapy for the treatmentof tumors with Aurora kinase amplification. Herein we describe ourlead optimization efforts within a 7-azaindole-based series culminatingin the identification of GSK1070916 (17k). Key to the advancementof the series was the introduction of a 2-aryl group containing abasic amine onto the azaindole leading to significantly improvedcellular activity. Compound 17k is a potent and selective ATP-competitiveinhibitor of Aurora B and C with Ki* values of 0.38 卤 0.29 and 1.5卤 0.4 nM, respectively, and is >250-fold selective over Aurora A.Biochemical characterization revealed that compound 17k has an extremelyslow dissociation half-life from Aurora B (>480 min), distinguishingit from clinical compounds 1 and 2. In vitro treatment of A549 humanlung cancer cells with compound 17k results in a potent antiproliferativeeffect (EC50 = 7 nM). Intraperitoneal administration of 17k in micebearing human tumor xenografts leads to inhibition of histone H3phosphorylation at serine 10 in human colon cancer (Colo205) andtumor regression in human leukemia (HL-60). Compound 17k is beingprogressed to human clinical trials.