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PAC-1

产品号 S2738 公司名称 Selleck Chemicals
CAS号 315183-21-2 公司网站 http://www.selleckchem.com
分子式 C23H28N4O2 电 话 (877) 796-6397
分子量 392.49402 传 真 (832) 582-8590
纯 度 电子邮件 sales@selleckchem.com
保 存 -20°C Chembase数据库ID: 73221

产品价格信息

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产品别名

标题
PAC-1
IUPAC标准名
2-(4-benzylpiperazin-1-yl)-N'-[(1E)-[2-hydroxy-3-(prop-2-en-1-yl)phenyl]methylidene]acetohydrazide
IUPAC传统名
2-(4-benzylpiperazin-1-yl)-N'-[(1E)-[2-hydroxy-3-(prop-2-en-1-yl)phenyl]methylidene]acetohydrazide
别名
Procaspase activating compound 1

产品登记号

CAS号 315183-21-2

产品性质

作用靶点 Caspase
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 PAC-1 is a potent procaspase-3 activator with EC50 of 0.22 μM.
Targets Procaspase-3
IC50 0.22 μM [1]
In Vitro PAC-1 activates procaspase-7 in a less efficient manner with EC50 of 4.5 μM. Elevated caspase 3 level in cancer cell lines allows PAC-1 to selectively induce apoptosis in a manner proportional to procaspase-3 concentration with IC50 of 0.35 μM for NCI-H226 cells to ~3.5 μM for UACC-62 cells. PAC-1 induces apoptosis in the primary cancerous cells with IC50 values of 3 nM to 1.41 μM, more potently than in the adjacent noncancerous cells with IC50 of 5.02 μM to 9.98 μM, which is also directly related to the distinct procaspase-3 concentration. [1] PAC-1 activates procaspase-3 by chelating zinc ions, thus relieving the zinc-mediated inhibition and allowing procaspase-3 to auto-activate itself to caspase-3. [2] PAC-1 is capable to induce cell death in Bax/Bak double-knockout cells and Bcl-2 and Bcl-xL-overexpressing cells with the same efficacy as its wild-type counterpart in a delayed manner. PAC-1 induces cytochrome c release in a caspase-3 independent manner, which subsequently triggers downstream caspase-3 activation and cell death. PAC-1 can not induce cell death and caspase-3 activation in Apaf-1 knockout cells, suggesting that apoptosome formation is essential for caspase-3 activation by PAC-1-mediated cell death. [3]
In Vivo Administration of PAC-1 at 5 mg with low and steady releasing significantly inhibits the growth of ACHN renal cancer xenograft in mice. Oral administration of PAC-1 (50 or 100 mg/kg) significantly retards tumor growth of NCI-H226 lung cancer xenograft in a dose-dependent manner, and markedly prevents the cancer cells from infiltrating the lung tissue. The in vivo anti-tumor effect of PAC-1 is ascribed to procaspase-3 activation and subsequently apoptosis induction consistent with the activity in vitro. [1]
Clinical Trials
Features PAC-1 is the first small molecule known to directly activate procaspase-3 to caspase-3
Protocol
Kinase Assay [1]
In vitro procaspase-3 activation Procaspase-3 is expressed and purified in Escherichia coli. Various concentrations of PAC-1 are added to 90 μL of a 50 ng/mL of procaspase-3 in caspase assay buffer in a 96-well plate, The plate is incubated for 12 hours at 37 °C. A 10 μL volume of a 2 mM solution of caspase-3 peptidic substrate acetyl Asp-Glu-Val-Asp-p-nitroanilide (Ac-DEVD-pNa) in caspase assay buffer is then added to each well. The plate is read every 2 minutes at 405 nm for 2 hours in a Spectra Max Plus 384 well plate reader. The slope of the linear portion for each well is determined, and the relative increase in activation from untreated control wells is calculated.
Cell Assay [1]
Cell Lines U-937, HL-60, CRL-1872, ACHN, NCI-H226, Hs888Lu, Hs578Bst, MCF-10A, SK-MEL-5, BT-20, MDA-MB-231, UACC-62, SK-N-SH, B16-F10 , Hs 578t, and PC-12
Concentrations Dissolved in DMSO, final concentrations ~100 μM
Incubation Time 72 hours
Methods Cells are exposed to various concentrations of PAC-1 for 72 hours. Cell death is quantified by the addition of MTS/PMS CellTiter 96 Cell Proliferation Assay reagent. The plates are incubated at 37 °C for approximately 1 hour (until the colored product formed), and the absorbance is measured at 490 nm.
Animal Study [1]
Animal Models Ovariectomized female athymic BALB/c (nude, nu/nu) mice injected subcutaneously with ACHN cells, male athymic BALB/c nude mice injected subcutaneously with NCI-H226 cells, and male athymic BALB/c–/– mice injected intravenously with NCI-H226 cells
Formulation Mixed with cholesterol and pelleted into a 3-mm-diameter 20-mg (total weight) pellet, or dissolved in a mixture of 24:1 vegetable oil/DMSO
Doses ~100 mg/kg
Administration Pellet implantation subcutaneously or oral gavage
References
[1] Putt KS, et al. Nat Chem Biol, 2006, 2(10), 543-550.
[2] Peterson QP, et al. J Mol Biol, 2009, 388(1), 144-158.
[3] Seervi M, et al. Cell Death Dis, 2011, 2, e207.