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PKI587

产品号 S2628 公司名称 Selleck Chemicals
CAS号 1197160-78-3 公司网站 http://www.selleckchem.com
分子式 C32H41N9O4 电 话 (877) 796-6397
分子量 615.72584 传 真 (832) 582-8590
纯 度 电子邮件 sales@selleckchem.com
保 存 -20°C Chembase数据库ID: 73116

产品价格信息

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产品别名

标题
PKI587
IUPAC标准名
3-{4-[bis(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-1-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}urea
IUPAC传统名
3-{4-[bis(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-1-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}urea
别名
PKI 587

产品登记号

CAS号 1197160-78-3

产品性质

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

产品详细信息

详细说明 (English)
Research Area
Description Cancer
Biological Activity
Description PKI-587 is a highly potent dual inhibitor of PI3Kα, PI3Kγ and mTOR with IC50 of 0.4 nM, 5.4 nM and 1.6 nM, respectively.
Targets PI3K-α PI3K-γ mTOR
IC50 0.4 nM 5.4 nM 1.6 nM [1]
In Vitro PKI-587 shows potent inhibitory activity against PI3K-α, PI3K-γ and mTOR with IC50 of 0.4 nM, 5.4 nM and 1.6 nM, respectively. Furthermore, PKI-587 also exhibits its potency against the most frequently occurring mutant forms of PI3Kα, notably the H1047R and E545K with IC50 of 0.6 nM and 0.6 nM, respectively. [1] Correlated with suppression of phosphorylation of PI3K/mTOR signaling pathway proteins, PKI-587 causes tumor cell growth inhibition in MDA-361 and PC3-MM2 cell lines with IC50 of 4 nM and 13.1 nM, respectively. [1]
In Vivo In nude mice, PKI-587 treatment at 25 mg/kg iv leads to low plasma clearance (7 (mL/min)/kg), high volume of distribution (7.2 L/kg), and long half-life, (14.4 hours). In the MDA-361 xenograft model, PKI-587 produces potent antitumor efficacy with the minimum efficacious dose (MED) of 3 mg/kg against MDA-361 tumors and maximum tolerated single dose (MTD) of 30 mg/kg. While in the H1975 (non-small-cell lung carcinoma, mutant EGFR [L858R, T790M]) xenograft model, PKI-587 at 25 mg/kg for 7 weeks results in 90% survival of the group treated. [1]
Clinical Trials PKI-587 is currently in Phase I clinical trials in patients with solid tumors.
Features
Combination Therapy
Description Combination of PKI-587 and Sorafenib shows a synergistic inhibitory effect on EGF-stimulated Huh7 proliferation compared with single therapy, and inhibits all the tested kinases in the Ras/Raf/MAPK and PI3K/Akt/mTOR pathways. [2]
Protocol
Kinase Assay [1]
PI3K and mTOR kinase assay Enzyme assays are done in fluorescent polarization (FP) format, adapted from the Echelon K-1100 PI3K FP assay kit protocol. Human class I PI3Ks and PI3K-α mutants (E545K and H1047R) are produced in Sf9 or purchased from Upstate Biotech. GST-GRP1 (murine) is produced in Escherichia coli and isolated by GST-Sepharose. Assay buffers are reaction buffer [20 mM HEPES (pH 7.1), 2 mM MgCl2, 0.05% CHAPS, and 0.01% β-mercaptoethanol] and stop/detection buffer [100 mM HEPES (pH 7.5), 4 mM EDTA, 0.05% CHAPS]. FP reaction is run for 30 minutes at room temperature in 20 μL of reaction buffer containing 20 μM phosphatidylinositol 4,5-bisphosphate (PIP2), 25 μM ATP, and <4% dmso.="" fp="" reaction="" is="" stopped="" with="" 20="" μl="" of="" stop/detection="" buffer="" (10="" nm="" probe="" and="" 40="" nm="" gst-grp),="" and="" after="" 2="" hours,="" data="" are="" collected="" using="" an="" envision="" plate="" reader.="" the="" routine="" assays="" with="" purified="" flag-tor="" (fl="" and="" 3.5)="" are="" performed="" in="" 96-well="" plates="" as="" follows.="" enzymes="" are="" first="" diluted="" in="" kinase="" assay="" buffer="" (10="" mm="" hepes="" (ph="" 7.4),="" 50="" mm="" nacl,="" 50="" mm="" β-glycerophosphate,="" 10="" mm="">2, 0.5 mM DTT, 0.25 μM microcystin LR, and 100 μg/mL BSA). To each well, 12 μL of the diluted enzyme is mixed briefly with 0.5 μL test inhibitor or control vehicle dimethyl sulfoxide (DMSO). The kinase reaction is initiated by adding 12.5 μL kinase assay buffer containing ATP and His6-S6K to give a final reaction volume of 25 μL containing 800 ng/mL FLAG-TOR, 100 μM ATP, and 1.25 μM His6-S6K. The reaction plate is incubated for 2 hours (linear at 1–6 hours) at room temperature with gentle shaking and then terminated by adding 25 μL Stop buffer (20 mM Hepes (pH 7.4), 20 mM EDTA, and 20 mM EGTA).
Cell Assay [1]
Cell Lines MDA-361 and PC3-MM2
Concentrations 0-10 μM
Incubation Time 72 hours
Methods Cells are plated in 96-well culture plates at about 3000 cells per well. One day following plating, PKI-587 is added to cells. Three days after PKI-587 treatment, viable cell densities are determined by measuring metabolic conversion (by viable cells) of the dye MTS, a previously established cell proliferation assay. For each assay, MTS and PMS stocks are freshly thawed and mixed (MTS/PMS, 20:1). The MTS/PMS mixture is then added to 96-well cell plates at 20 μL/well, and plates are incubated for 1 hour–2 hours in cell culture incubator. MTS assay results are read in a 96-well format plate reader by measuring absorbance at 490 nm. The effect of each PKI-587 treatment is calculated as a percentage of control cell growth obtained from vehicle-treated cells grown in the same culture plate.
Animal Study [1]
Animal Models MDA-361 and H1975 cells are injected subcutaneously into the nude mice.
Formulation Dissolved in 5% dextrose [D5/W], 0.3% lactic acid.
Doses ≤30 mg/kg
Administration Administered via i.v.
References
[1] Venkatesan AM, et al. J Med Chem. 2010, 53(6), 2636-2645.
[2] Gedaly R, et al. J Surg Res. 2011, doi.org/10.1016/j.jss.2011.10.045.