Home Apoptosis Caspase activator PAC-1 For research use only.

PAC-1

PAC-1 is a potent procaspase-3 activator with EC50 of 0.22 μM and the first small molecule known to directly activate procaspase-3 to caspase-3.

PAC-1 Chemical Structure

PAC-1 Chemical Structure

CAS No. 315183-21-2

Purity & Quality Control

PAC-1 Related Products

Signaling Pathway

Caspase Signaling Pathways

Caspase Signaling Pathway

Biological Activity

Description PAC-1 is a potent procaspase-3 activator with EC50 of 0.22 μM and the first small molecule known to directly activate procaspase-3 to caspase-3.
Features The first small molecule known to directly activate procaspase-3 to caspase-3.
Targets
Procaspase-3 [1]
0.22 μM(EC50)
In vitro
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]
Kinase Assay 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 Research 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
Method 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 n
Experimental Result Images Methods Biomarkers Images PMID
Western blot Ero1-Lα / Calnexin / IRE-1α / p-eIF2α / eIF2α / CHOP 24357799
Immunofluorescence Hif1α p-H2AX / Rad51 30287840
In Vivo
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]
Animal Research 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
Dosages ~100 mg/kg
Administration Pellet implantation subcutaneously or oral gavage
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT05967741 Recruiting
Platelet Aggregation Spontaneous|Vascular Thrombosis
University of California Davis
 July 20 2023 Not Applicable
NCT03927248 Withdrawn
Metastatic Renal Cell Carcinoma
HealthPartners Institute
 September 2020 Phase 1|Phase 2
NCT03441412 Completed
Healthy Volunteers
Vastra Gotaland Region|Gothia Forum - Center for Clinical Trial|Uppsala University
 February 28 2018 Phase 1

Chemical Information & Solubility

Molecular Weight 392.49 Formula

C23H28N4O2
CAS No. 315183-21-2 SDF Download PAC-1 SDF
Smiles C=CCC1=C(C(=CC=C1)C=NNC(=O)CN2CCN(CC2)CC3=CC=CC=C3)O
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 78 mg/mL ( (198.73 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 78 mg/mL

Water : Insoluble


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In vivo
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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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