Afuresertib (GSK2110183)

Catalog No.S7521

Afuresertib (GSK2110183) Chemical Structure

Molecular Weight(MW): 427.32

Afuresertib (GSK2110183) is a potent, orally bioavailable Akt inhibitor with Ki of 0.08 nM, 2 nM, and 2.6 nM for Akt1, Akt2, and Akt3, respectively. Phase 2.

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Cited by 2 Publications

1 Customer Review

  • Analysis of the mechanism of action of the enhanced anti‑tumor effect of the combination therapy of suboptimal doses of pomalidomide plus dexamethasone and afuresertib in MM cells. (A‑C) The altered expression of protein substrates was analyzed in two MM cell lines that were treated with suboptimal doses of PD, or AFU, or the PD and AFU combination. The XG‑7 and U266 cell lines were subjected to the indicated treatments for 48 and 72 h, respectively. (A) Caspases, (B) substrates related mainly to the working mechanism of IMiDs, (C) substrates mainly related to the working mechanism of afuresertib, and (D) two primary MM cell cultures, were subjected to the analysis in the same manner as the two MM cell lines. In the expression panel of p‑FoxO3a/FoxO1, the upper band represents p‑FoxO3a and the lower band represents p‑FOXO1. PD, pomalidomide plus dexamethasone; AFU, Afuresertib; MM, multiple myeloma; IMiDs, immunomodulatory drugs.

    ONCOLOGY LETTERS, 2018, https://doi.org/10.3892/ol.2018.8501. Afuresertib (GSK2110183) purchased from Selleck.

Purity & Quality Control

Choose Selective Akt Inhibitors

Biological Activity

Description Afuresertib (GSK2110183) is a potent, orally bioavailable Akt inhibitor with Ki of 0.08 nM, 2 nM, and 2.6 nM for Akt1, Akt2, and Akt3, respectively. Phase 2.
Targets
Akt1 [1]
(Cell-free assay)		 Akt2 [1]
(Cell-free assay)		 Akt3 [1]
(Cell-free assay)
0.08 nM(Ki) 2 nM(Ki) 2.6 nM(Ki)
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.[1]
Assay
Methods Test Index PMID
Western blot
p-GSK3 / GSK3 / p-PRAS40 / PRAS40 / p-FOXO / p-Casp9 / p-AKT / AKT / p-MEK / p-ERK / Erk ; 

PubMed: 24978597     


BT474 (left) and LNCaP (right) cell lines were treated with DMSO or GSK2110183 for 1 h. Western analysis was performed to assay levels of phosphorylated and total GSK-3, PRAS40, AKT and ERK, phosphorylated Foxo, Caspase 9, and MEK. Tubulin was used as a loading control. 

ATG3 / ATG12 / LC3B ; 

PubMed: 30867818     


Alterations in autophagy-related proteins induced by AKT inhibition.

24978597 30867818
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.[1]

Protocol

Kinase Assay:[1]
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Potency (Ki*) of afuresertib:

The true potency (Ki*) of the inhibitor is initially determined at low enzyme concentrations (0.1 nM AKT1, 0.7 nM AKT2, and 0.2 nM AKT3) using a filter binding assay and then confirmed with progress curve analysis. In the filter binding assay, a pre-mix of enzyme plus inhibitor is incubated for 1 h and then added to a GSKα peptide (Ac-KKGGRARTSS-FAEPG-amide) and [γ33P] ATP. Reactions are terminated after 2 h and the radio labeled AKT peptide product is captured in a phospho-cellulose filter plate. Progress curve analysis utilizes continuous real-time fluorescence detection of product formation using the Sox-AKT-tide substrate (Ac-ARKRERAYSF-d-Pro-Sox-Gly-NH2).
Cell Research:[1]
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  • Cell lines: Hematological cell lines and solid tumor cell lines
  • Concentrations: 30 μM
  • Incubation Time: 72 h
  • Method: A 3-day proliferation assay using CellTiter-Glo is performed to measure the growth inhibition by the compounds at 0-30 μM. Cell growth is determined relative to untreated (DMSO) controls. EC50’s are calculated from inhibition curves using a 4- or 6-parameter fitting algorithm in the Assay Client application.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: Female athymic nude and SCID mice bearing SKOV3 or BT474 tumors
  • Formulation: 20% polyethylene glycol (PEG) 400/1% DMSO
  • Dosages: 100 mg/kg
  • Administration: p.o.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 85 mg/mL (198.91 mM)
Ethanol 85 mg/mL (198.91 mM)
Water Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 427.32
Formula

C18H17Cl2FN4OS
CAS No. 1047644-62-1
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04060394 Recruiting Drug: Phase I and Phase II: LAE001/prednisone + afuresertib Metastatic Castration-resistant Prostate Cancer Laekna Limited September 2019 Phase 1|Phase 2
NCT02235740 Terminated Drug: Afuresertib|Drug: Carfilzomib Cancer Novartis|Amgen November 2014 Phase 1
NCT02240212 Completed Drug: Afuresertib|Drug: Paclitaxel Cancer Novartis Pharmaceuticals|Novartis October 2014 Phase 1
NCT02177682 Terminated Drug: Afuresertib Neoplasms Haematologic Novartis Pharmaceuticals|Novartis August 13 2014 Phase 1
NCT02040480 Completed Drug: GSK2110183 Gelatin Capsule|Drug: GSK2110183 IR Tablet Cancer GlaxoSmithKline February 5 2014 Phase 1

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID