Vevorisertib trihydrochloride (C09-1184-797)

Vevorisertib (ARQ 751) trihydrochloride is a selective, allosteric, pan- AKT and AKT1-E17K mutant inhibitors. Vevorisertib trihydrochloride potently inhibit phosphorylation of AKT . Vevorisertib trihydrochloride has Kd values of 1.2 nM and 8.6 nM for AKT1 and AKT1-E17K, respectively. Vevorisertib trihydrochloride has IC 50 values of 0.55, 0.81, and 1.3 nM for AKT1 , AKT2 , and AKT3 , respectively. Vevorisertib trihydrochloride can be used for the research of cancerIn VitroVevorisertib trihydrochloride (0, 12, 33, 111, 333, 1000 nM, 2 hours) inhibits phosphorylation of AKT1-E17K. Vevorisertib trihydrochloride (1 μM for 2 hours; NIH 3T3 cells are transfected with either pcDNAAKT-WT-GFP or pcDNA-E17K-GFP) inhibits plasma membrane translocation of AKT-WT and AKT1-E17K irrespective of the presence of growth factors. Vevorisertib trihydrochloride (5 μM) exhibites 57% inhibition of full-length AKT1. Vevorisertib trihydrochloride (0, 0.012, 0.037, 0.11, 0.33, 1 μM; 2 hours) shows a dose-dependent effect on mTORC1 and AKT direct substrates including PRAS40, GSK3β, FOXO, BAD, and AS160 in cancer cell lines. Vevorisertib trihydrochloride has anti-proliferative effect on esophageal, breast, and head and neck cancer cells (GI 50 < 1 μM). Vevorisertib trihydrochloride exhibits strong anti-proliferative activity in PIK3CA mutant cell lines. Vevorisertib trihydrochloride (MK-4440)/imatinib mesylate (IM) combination shows cell cycle arrest, and increases cell death of gastrointestinal stromal tumor (GIST) cells. Vevorisertib trihydrochloride exhibits strong anti-proliferative activity in PIK3CA mutant cell lines: Breast Cancer Cell Lines GI 50 (nM) PIK3CA ER PR HER2 T47D 1.05 H1047R + + - EFM-19 1.54 H1047R + + - MCF-7 2.20 E545K + + - BT474 3.25 K111N + + + MDA-MB-453 6.05 H1047R - - + MCE has not independently confirmed the accuracy of these methods. They are for reference only. Western Blot AnalysisCell Line: 293T cells (transiently transfected with pcDNA-E17K-GFP) Concentration: 0, 12, 33, 111, 333, 1000 nM Incubation Time: 2 hours Result: Inhibited phosphorylation of AKT1-E17K. Western Blot AnalysisCell Line: Cancer cell lines: MDA-MB 453 (PIK3CAH1047R; Her2 amp), NCI-H1650 (PTEN ), KU-19-19 (AKT1-E17K&E49K; NRas Q61R) Concentration: 0, 0.012, 0.037, 0.11, 0.33, 1 μM Incubation Time: 2 hours Result: Showed a dose-dependent effect on mTORC1 and AKT direct substrates including PRAS40, GSK3β, FOXO, BAD, and AS160.In VivoVevorisertib trihydrochloride (25, 50 and 75 mg/kg; p.o.; 5 days dosing followed by a 4 day dosing holiday for 20 days) shows potent tumor growth inhibition of 68, 78 and 98%, respectively . Vevorisertib trihydrochloride (5, 10, 20, 40, 80, and 120 mg/kg; p.o. daily for ten days) shows tumor growth inhibition of 29, 33, 50, 73, 83, and 92%, respectively . Vevorisertib trihydrochloride reachs C max plasma concentrations of ≥2 μM . Vevorisertib trihydrochloride is generally well-tolerated at dose levels up to 120 mg/kg . Vevorisertib trihydrochloride (MK-4440)/IM combination shows superior efficacy in an IM-sensitive preclinical model of GIST compared with either single agent. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Endometrial PDX mouse xenograft models (AKT1-E17K mutation tumor fragments subcutaneously implanted in athymic nude mice; tumor volume of approximately 200 mm 3 ) Dosage: 25, 50 and 75 mg/kg Administration: p.o.; 5 days dosing followed by a 4 day dosing holiday for 20 days Result: Showed potent tumor growth inhibition of 68, 78 and 98%, respectively. Animal Model: AN3CA mouse xenograft models (female NCr nu/nu mice with 250 mm 3 tumors size) Dosage: 5, 10, 20, 40, 80, and 120 mg/kg Administration: p.o.; daily for ten days Result: Showed tumor growth inhibition of 29, 33, 50, 73, 83, and 92%, respectively.Form:SolidIC50& Target:Akt1 0.55 nM (IC 50 ) Akt2 0.81 nM (IC 50 ) Akt3 1.31 nM (IC 50 ) Akt1 1.2 nM (Kd) Akt1 E17K 8.6 nM (Kd). Specifications and Purity: 99%. Molecular Formula: C35H41Cl3N8O. Molecular Weight: 696.11.