PK11007

In the concentration range of 15 to 30 µM, treatment with PK11007 (0-120 µM; 24 hours; four p53 wild-type cell lines and four p53 mutant cell lines) significantly reduced the viability of the mutant p53 cell lines MKN1 (V143A), HUH-7 (Y220C), NUGC-3 (Y220C), and SW480 (R273H/P309S). PK11007 mostly causes cell death that is not dependent on caspase [1]. In NUGC-3 (p53-Y220C), HUH-7 (p53-Y220C), and MKN1 (p53-V143A) cells, PK11007 (0-60 µM; 3 hours or 6 hours; NUGC-4, NUGC-3, MKN1, HUH-6, and HUH-7 cancer cells) treatment upregulates protein levels of p53 target genes p21, MDM2, and p53 PUMA in a concentration-dependent manner. This suggests a partial restoration of the transcriptional activity of the unstable p53 mutant. Increased MDM2, PUMA, and p21 protein levels in HUH-6 and NUGC-4 cells demonstrate that PK11007 also boosts p53 function in these cells [1]. After treating three mutant p53 cell lines with PK11007 (15–20 µM; 4.5 or 6 hours; MKN1, HUH-7, NUGC-3, HUH-6 cells), transcription of p53 target genes increased. PUMA and p21 mRNA levels were elevated twofold following NOXA treatment of NUGC-3, MKN, and HUH-7 cells, as well as the latter two cells. MKN1 and NUGC-3 cells have halved MDM2 levels [1]. Depletion of glutathione intensifies the decline in PK11007 activity. PK11007 was incubated with NUGC-3, NUGC-4, HUH-6, HUH-7, and MKN1 cells for two hours in order to see if it also raised ROS levels. All cell lines showed an increase in ROS levels after two hours. Nevertheless, the rise in ROS at 60 µM PK11007 in mutant p53 cells MKN1, HUH-7, and NUGC-3 was greater than in NUGC-4 and HUH-6 cells, suggesting that the mutant p53 cell lines were more susceptible to PK11007. Increased induction of ROS is mediated. MKN1 cells had ROS levels that are at least twice as high as those of other cell lines, both basal and PK11007-induced [1]. In line with its capacity to reactivate mutant p53, PK11007 suppresses cell growth, triggers apoptosis, and modifies genes related to cell death [2].

Cell viability assay [1]
Cell Types: p53 wild-type cell lines (WI-38, HUH-6, NUGC-4, SJSA-1) and p53 mutant cell lines (HUH-7, NUGC-3, SW480, MKN1) concentration ) , NUGC-3 (Y220C) and SW480 (R273H/P309S), and the p53 WT cell line SJSA-1 at concentrations ranging from 15 to 30 µM. p53 WT cancer cell lines HUH-6, NUGC-4 and WI-38 were less sensitive, with diminished cell viability only at high concentrations of the compound (60 and 120 µM).

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Western Blot Analysis[1]
Cell Types: NUGC-4, NUGC-3, MKN1, HUH-6, and HUH-7 Cancer cell
Tested Concentrations: 0 μM, 15 μM, 30 μM, 60 μM
Incubation Duration: 3 hrs (hours) or 6 hrs (hours)
Experimental Results: Protein levels of p53 target genes p21, MDM2 and PUMA in NUGC-3 (p53-Y220C), HUH-7 (p53-Y220C) and MKN1 (p53-V143A) cells were upregulated in a concentration-dependent manner. Increased MDM2, PUMA, and p21 protein levels indicated that p53 activity was also increased in HUH-6 and NUGC-4 cells.

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RT-PCR[1]
Cell Types: MKN1, HUH-7, NUGC-3, HUH-6 Cell
Tested Concentrations: 15 μM, 20 μM Incub

[1]. Bauer MR, et al. 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells. Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):E5271-80.
[2]. Synnott NC, et al. Mutant p53 as a therapeutic target for the treatment of triple-negative breast cancer: Preclinical investigation with the anti-p53 drug, PK11007. Cancer Lett. 2018 Feb 1;414:99-106

C15H11CLFN5O3S2

427.85

874146-69-7

O=C(C1=NC(S(=O)(CC2=CC=C(F)C=C2)=O)=NC=C1Cl)NC3=NN=C(C)S3

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.86 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.86 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)