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GSK1059615

产品号 S1360 公司名称 Selleck Chemicals
CAS号 958852-01-2 公司网站 http://www.selleckchem.com
分子式 C18H11N3O2S 电 话 (877) 796-6397
分子量 333.36384 传 真 (832) 582-8590
纯 度 电子邮件 sales@selleckchem.com
保 存 -20°C Chembase数据库ID: 72633

产品价格信息

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产品别名

标题
GSK1059615
IUPAC标准名
(5Z)-5-{[4-(pyridin-4-yl)quinolin-6-yl]methylidene}-1,3-thiazolidine-2,4-dione
IUPAC传统名
(5Z)-5-{[4-(pyridin-4-yl)quinolin-6-yl]methylidene}-1,3-thiazolidine-2,4-dione

产品登记号

CAS号 958852-01-2

产品性质

作用靶点 PI3K
作用靶点 mTOR
成盐信息 Free Base
溶解度 DMSO
保存条件 -20°C

产品详细信息

详细说明 (English)
Research Area
Description Cancer
Biological Activity
Description GSK1059615 is a novel and dual inhibitor of PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ and mTOR with IC50 of 0.4 nM, 0.6 nM, 2 nM, 5 nM and 12 nM, respectively.
Targets PI3Kα PI3Kβ PI3Kδ PI3Kγ mTOR
IC50 0.4 nM 0.6 nM 2 nM 5 nM 12 nM [1]
In Vitro The pyridinylquinoline derivative GSK1059615 is a novel, ATP-competitive, and reversible inhibitor of the class I family of PI3Ks. GSK1059615 inhibits PI3K signaling, induces G1 arrest and apoptosis, especially in breast tumor cells. [2] Data summarized in another review also shows that GSK1059615 inhibits PI3Kα, β, γ and δ, with Ki of 0.42 nM, 0.6 nM, 0.47 nM and 1.7 nM, respectively. [3] Another report shows that GSK1059615 inhibits PI3Kα with IC50 of 2 nM. In T47D and BT474 cancer cells, GSK1059615 inhibits the phosphorylation of Akt at S473, with IC50 of 40 nM. [4]
In Vivo In xenograft mice models of BT474 or HCC1954 breast cancer cells, GSK1059615 (25 mg/kg) effectively inhibits tumor growth. [3]
Clinical Trials A Phase I clinical trial for GSK1059615 for solid tumors has been terminated.
Features GSK1059615 is a novel, ATP-competitive, and reversible inhibitor of both PI3Kα, β, δ, and γ, and mTOR.
Protocol
Kinase Assay [4]
HTRF In vitro Profiling Assays for PI3K Inhibition The measurement of the GSK1059615-dependent inhibition of the PI3Ks is accessed using a HTRF based PI3K profiling assay kit. 400 pM enzyme is used in PI3Kα and δ assays, 200 pM in PI3Kβ assays, and 1 nM in PI3Kγ assay. In addition, the PI3Kα, β, and δ assays are run with 150 mM NaCl and 100 μM ATP, while the PI3Kγ assay is run with no NaCl and 15 μM ATP. All reactions are run at 10 μM PIP2. GSK1059615 is serially diluted (3-fold in DMSO), and 50 nL is transferred to a 384-well low-volume assay plate. PI3K Reaction Buffer is prepared by diluting the stock 1:4 with de-ionized water. Freshly prepared DTT is added at a final concentration of 5 mM on the day of use. Enzyme addition and GSK1059615 pre-incubation are initiated by the addition of 2.5 μL of PI3K in reaction buffer. Plates are incubated at room temperature for 15 min. Reactions are initiated by addition of 2.5 μL of 2× substrate solution (PIP2 and ATP in 1× reaction buffer). Plates are incubated at room temperature for one hour. Reactions are quenched by the addition of 2.5 μL of stop solution. The quenched reactions are then processed to detect product formation by adding 2.5 μL of Detection Solution. Following a 1-hour incubation in the dark, the HTRF signal is measured on the Envision plate reader set for 330nm excitation and dual emission detection at 620nm (Eu) and 665nm (APC). The IC50 value is then obtained.
Cell Assay [4]
Cell Lines T47D and BT474 cells
Concentrations 0–1 μM, serially diluted (3-fold) in DMSO
Incubation Time 30 min
Methods Cells are plate at a density of 1 × 104 cells per well in clear flat-bottomed 96-well plates and incubated overnight. Then, GSK1059615 is added and the plates are incubated for 30 min. At the end of incubation, media is aspirated from the plates, and the plate is wash once with cold PBS. 80 μL MSD Lysis buffer is added into each well and the plates are incubated on a shaker at 4 °C for at least 30 min. For Akt duplex assay, plates are washed with 200 μL/well wash buffer for 4 times and tapped on paper towel to blot. Then, 60 μL lysates is added to each well and the plates are incubated on shaker at room temperature for 1 hour. After another 4 times washing, antibody is added (25 μL per well) and the plates are incubated on shaker for 1 hour and washed again. Finally, Read Buffer is added (150 μL per well) and the plates are read immediately. IC50 values are then obtained.
Animal Study [3]
Animal Models Xenograft mice models of BT474 or HCC1954 cells
Formulation
Doses 25 mg/kg
Administration Oral gavage
References
[1] Carnero A. Expert Opin Investig Drugs, 2009, 18(9), 1265-1277.
[2] Auger KR, et al. EORTC-NCI-AACR, 2008.
[3] Maira SM, et al. Curr Top Microbiol Immunol, 2010, 347, 209-239.
[4] Knight SD, et al. ACS Med Chem Lett, 2010, 1(1), 39-43.