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A66 目录号 GC17550

P110α inhibitor

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥1,071.00
现货
5mg
¥914.00
现货
10mg
¥1,680.00
现货
50mg
¥5,124.00
现货

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Sample solution is provided at 25 µL, 10mM.

质量管理

Quality Control & SDS

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实验参考方法

Kinase experiment:

IC50 values are evaluated using the PI3K (human) HTRF Assay. p85α/p110δ is obtained from Invitrogen. All other isoforms are produced in-house by co-expressing full-length human p85α with the indicated human full-length catalytic subunit containing a histidine tag at the N-terminus to allow purification. The PI3Ks are titrated and used at a concentration between their EC65-EC80 values. PI3K activity in immunoprecipitates is assayed using an antibody to the N-SH2 (N-Src homology 2) domain of p85α. Assays for other lipid kinases and protein kinases are performed by the National Centre for Protein Kinase Profiling and Invitrogen Drug Discovery Services[1].

Animal experiment:

Mice[1] Age-matched specific pathogen-free Rag1-/- or NIH-III mice are subcutaneously inoculated on the right flank with 5×106 U87MG, SK-OV-3 or HCT-116 cells in PBS. Tumour diameter as measured by electronic calipers is used to calculate tumour volume (mm3) based on the formula (L×w2)×π/6 (where L=longest tumour diameter and w=perpendicular diameter). A66 is administered in 20% 2-hydroxypropyl-β-cyclodextrin in water, whereas BEZ-235 is administered in 10% ethanol. Control mice are administered the A66 dosing vehicle alone. The drugs are dosed by intraperitoneal injection as the free base equivalent at a dosing volume of 10 mL/kg of body weight. For tumour pharmacodynamic studies, mice are administered a single dose of A66 or the control vehicle when tumors reached approximately 8-9 mm in diameter. Animals are killed 1 or 6 h after dosing and the tumors are removed, biopulverized and assayed for protein concentration. For antitumor efficacy studies, dosing began when tumors are well established, averaging approximately 7 mm in diameter. Doses are administered once daily (QD) or twice daily (BID) with injections separated by a minimum of approximately 8 h. Different dosing schedules are used for the three xenograft models depending on the rate of tumor growth and the body weight tolerance of control mice. Animals are dosed daily for 21 days or twice daily for 16 days (SK-OV-3), daily for 14 days (U87MG) and daily for 7 days (HCT-116). Animals are monitored daily for any signs of emerging toxicity and body weight is recorded. Mice are killed if they developed moderate signs of toxicity or if body weight loss exceeded 20% of starting weight. TGI (tumour growth inhibition) is calculated on the final day of dosing by determining the relative tumour size of drug-treated mice as a percentage of the average relative tumour size of control mice. The statistical significance of TGI values is determined by one-way ANOVA with Bonferroni multiple comparison analysis using GraphPad Prism 5.02.

References:

[1]. Jamieson S, et al. A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types. Biochem J, 2011, 438(1), 53-62.
[2]. Sun M, et al. Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha. Proc Natl Acad Sci U S A, 2010, 107(35), 15547-15552.

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Chemical Properties

Cas No. 1166227-08-2 SDF
别名 A 66; A-66
化学名 (2S)-1-N-[5-(2-tert-butyl-1,3-thiazol-4-yl)-4-methyl-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide
Canonical SMILES CC1=C(SC(=N1)NC(=O)N2CCCC2C(=O)N)C3=CSC(=N3)C(C)(C)C
分子式 C17H23N5O2S2 分子量 393.53
溶解度 ≥19.7mg/mL in DMSO 储存条件 Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

产品描述

A66 is a potent and selective p110α inhibitor with IC50 of 32 nM.
P110α  is the catalytic subunit of a class I Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic that is composed of a 85 kDa regulatory subunit and a 110 kDa catalytic subunit.
A66 treatment inhibits phosphorylation of Akt/PKB in certain cell lines that have H1047R mutation in PIK3CA and high levels of p110a [1]. A66 prolonged treatment reduced phosphorylation of S6K on Thr389, a marker of activity of this kinase and prevent IRS downregulation induced by chronic insulin treatment in both C2C12 myoblasts and 3T3-L1 adipocytes [2].
The component has also been used extensively in various animal models to study the role of PI3K. For instance, inhibition of p110α by A66 treatment was shown to reduce tumor growth of certain cell lines in in vivo xenograft models [1]. Chronic pharmacological inhibition of p110α through A66 treatment protects from insulin resistance induced by sustained metabolic stress [2]. In the mouse model of mammary fat pad transplantation of athymic mice with primary tumors, treatment of transplanted tumor-bearing mice with A66 reduce tumor growth dramatically [3].
References:
1.Jamieson S, Flanagan JU, Kolekar S, Buchanan C, Kendall JD, Lee WJ, et al. A drug targeting only p110alpha can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types. Biochem J 2011,438:53-62.
2.Foukas LC, Bilanges B, Bettedi L, Pearce W, Ali K, Sancho S, et al. Long-term p110alpha PI3K inactivation exerts a beneficial effect on metabolism. EMBO Mol Med 2013,5:563-571.
3.Utermark T, Rao T, Cheng H, Wang Q, Lee SH, Wang ZC, et al. The p110alpha and p110beta isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis. Genes Dev 2012,26:1573-1586.