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PF-AKT400  ≥95%

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包装规格：5mg 10mg 50mg 100mg in glass bottle
溶解性：溶于DMSO(≥100mg/mL）
产品描述：基本信息 产品编号： P11734 产品名称： PF-AKT400 CAS: 1004990-28-6   储存条件 粉末 -20℃ 四年     分子式： C20H22F2N6O 溶于液体 -80℃ 6个月 分子量： 400.43 -20℃ 1个月 化学名：  AKT protein kinase inhibitor;N-{[(3s)-3-Amino-1-(5-Ethyl-7h-Pyrrolo[2,3-D]pyrimidin-4-Yl)pyrrolidin-3-Yl]methyl}-2,4-Difluorobenzamide Solubility (25°C)：   体外:   DMSO   Ethanol   Water   体内(现配现用):   ＜1mg/ml表示微溶或不溶。 普西唐提供的所有化合物浓度为内部测试所得，实际溶液度可能与公布值有所偏差，属于正常的批间细微差异现象。 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；⼀旦配成溶液，请分装保存，避免反复冻融造成的产品失效。   制备储备液   浓度   溶液体积 质量   1mg   5mg   10mg 1mM 2.4973mL 12.4866mL 24.9732mL 5mM 0.4995mL 2.4973mL 4.9946mL 10mM 0.2497mL 1.2487mL 2.4973mL   生物活性 产品描述 一种有效的,ATP竞争性的选择性Akt抑制剂，对PKBα(IC50=0.5nM)的选择性比PKA (IC50=450nM)高900倍。 靶点 PKBα 0.5nM (IC50) PKA 450nM (IC50)   体外研究 PF-AKT400 (Compound 42) provides significantly enhanced selectivity for Akt relative to earlier leads such as spiroindoline 2.Free IC50 and EC50 values are estimated for phospho-S6 reduction (110nM) and Akt hyperphosphorylation (216nM),respectively.These values corresponded well to the cellular IC50 for PF-AKT400 in U87 cells measuring p-GSK-3α(310nM). 体内研究 PF-AKT400 is subsequently evaluated for modulation of Akt in tumors and in multiple in vivo mouse models of antitumor efficacy.It is active in a PC3 prostate carcinoma xenograft experiment,with 75% TGI observed at 100mg/kg b.i.d.dosing for 10 days.In a colorectal carcinoma (Colo205) xenograft study,PF-AKT400 produces 60% TGI at 150mg/kg b.i.d.after 10 days.Most intriguingly,in combination with Rapamycin (10mg/kg,ip),75mg/kg b.i.d.(10 days) of PF-AKT400 results in 98% TGI in an additional PC3 prostate carcinoma xenograft study compared to 56% TGI and 66% TGI with PF-AKT400 and Rapamycin as single agents.To define the in vivo potency of PF-AKT400 (Compound 42) in the PC3 xenograft model, oral administration of 25,75,and 100mg/kg PF-AKT400 is performed with blood and tumor sampling over time.Immunoblot analysis of detergentsoluble extracts derived from PC3 tumors shows a significant reduction of S6 phosphorylation,and hyperphosphorylation of Akt upon treatment at doses that produced significant tumor growth inhibition.Plasma drug concentrations peak rapidly after oral administration of doses between 25-100mg/kg (Tmax=0.5h).Peak PD responses of phospho-S6 and phospho-Akt are observed at approximately 2-4h and 1h post-administration of PF-AKT400,respectively.The time-course of PD marker response is well described by a PK/PD model at doses that ranged from no efficacy (25mg/kg) to maximal efficacy (100mg/kg).   推荐实验方法(仅供参考) 激酶实验： A fluorescence polarization IMAP type assay is used. An amount of 15μL of diluted PF-AKT400 (Compound 42) in DMSO is mixed with 60μL of reaction buffer (10mM Tris-HCl,pH 7.5,10mM MgCl2,0.1mM EGTA,0.01% Triton-X100,1mM DTT).Then 5μL of the compound/buffer mixture,10μL of a solution containing 4μM ATP and 40nM fluorescent-labeled Crosstide (Tamara-labeled GRPRTSSFAEG peptide),and 5μL of Akt1 protein (lacking the pleckstrin homology (PH) domain,containing an Asp at position 473,and prephosphorylated at Thr 308) in reaction buffer are combined.After a 90 min incubation,IMAP beads are added and plates are read (lamp filter,544nm;emission filter,615nm).The same procedure can be applied to full length Akt1 to provide similar results. All IC50 values are the geometric mean of at least n=2 determinations.   动物实验:   Mice Studies to describe the PK/PD relationship for PF-AKT400 are performed in male SCID/Beige mice bearing subcutaneous PC3 prostate carcinoma xenografts.Once tumors reach about ~300mm3 in size,PF-AKT400 is formulated in 0.5% methylcellulose vehicle and administered orally to 3 mice per dose group.Plasma and tumors are harvested over time,tumor lysates prepared,and the levels of phospho S6 reduction and phospho Akt induction are evaluated by immunoblot.
保存条件：-20℃

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