In vitro: Afuresertib inhibits the kinase activity of the E17K AKT1 mutant protein with EC50 of 0.2 nM. Afuresertib shows a concentration-dependent effect on multiple AKT substrate phosphorylation levels, including GSK3b, PRAS40, FOXO and Caspase 9. Overall 65% of the hematological cell lines are sensitive to afuresertib (EC50 < 1 μM). Among tested solid tumor cell lines, 21% have EC50 < 1 μM in response to afuresertib. In vivo: Mice bearing BT474 breast tumor xenografts are dosed with afuresertib (p.o.) at 10, 30 or 100 mg/kg daily which results in 8, 37 and 61% TGI, respectively. Mice bearing SKOV3 ovarian tumor xenografts are treated with 10, 30 and 100 mg/kg afuresertib which results in 23, 37 and 97% TGI, respectively.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||85 mg/mL in DMSO|
Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma.
Tolcher AW, et al. Cancer Chemother Pharmacol. 2015 Jan;75(1):183-9. PMID: 25417902.
The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma.
Spencer A, et al. Blood. 2014 Oct 2;124(14):2190-5. PMID: 25075128.
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Theaflavin 3,3'-digallate (TF3) is an antitumor agent.
Afuresertib hydrochloride is an orally bioavailable, potent and ATP-competitive inhibitor of the serine/threonine protein kinase Akt with potential antineoplastic activity.
Miransertib, also known as ARQ 092, is an oral activie, potent and selective AKT inhibitor with IC50 values: 5.0 nM (AKT1); 4.5 nM (AKT2); 16 nM (AKT3).
GSK2141795 is a potent and selective pan-Akt inhibitor with IC50 values of 180 nM for Akt1, 328 nM for Akt2, and 38 nM for Akt3 respectively (Clinical phase 1).
GDC-0068(RG 7440) 2Hcl is a highly selective pan-Akt inhibitor targeting Akt1/2/3 with IC50 of 5 nM/18 nM/8 nM, 620-fold selectivity over PKA.
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