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PK11007 is a novel and potent anti-p53 compound with anti-tumor activities through activation of unstable p53 (tumor suppressor p53). PK11007 acted by two routes: p53 dependent and p53 independent. PK11007 stabilized p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. Unstable p53 was reactivated by PK11007 in some cancer cell lines, leading to up-regulation of p53 target genes such as p21 and PUMA. More generally, there was cell death that was independent of p53 but dependent on glutathione depletion and associated with highly elevated levels of reactive oxygen species and induction of endoplasmic reticulum (ER) stress, as also found for the anticancer agent PRIMA-1(MET)(APR-246). PK11007 may be a lead for anticancer drugs that target cells with nonfunctional p53 or impaired reactive oxygen species (ROS) detoxification in a wide variety of mutant p53 cells.
| ln Vitro |
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].
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| Cell Assay |
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). 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. RT-PCR[1] Cell Types: MKN1, HUH-7, NUGC-3, HUH-6 Cell Tested Concentrations: 15 μM, 20 μM Incub |
| References |
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| Molecular Formula |
C15H11CLFN5O3S2
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| Molecular Weight |
427.86094212532
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| Exact Mass |
427
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| Elemental Analysis |
C, 42.11; H, 2.59; Cl, 8.29; F, 4.44; N, 16.37; O, 11.22; S, 14.99
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| CAS # |
874146-69-7
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| Related CAS # |
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| PubChem CID |
16446482
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| Appearance |
White to off-white solid powder
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| LogP |
2.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
629
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
IVZQUWCWXYFPOQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H11ClFN5O3S2/c1-8-21-22-14(26-8)20-13(23)12-11(16)6-18-15(19-12)27(24,25)7-9-2-4-10(17)5-3-9/h2-6H,7H2,1H3,(H,20,22,23)
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| Chemical Name |
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3372 mL | 11.6861 mL | 23.3721 mL | |
| 5 mM | 0.4674 mL | 2.3372 mL | 4.6744 mL | |
| 10 mM | 0.2337 mL | 1.1686 mL | 2.3372 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Biological effects of PK11007 on diverse cancer cell lines and one human fibroblast cell line.Proc Natl Acad Sci U S A.2016 Sep 6;113(36):E5271-80. |
Biological effects of 2-sulfonylpyrimidines on diverse cell lines.Proc Natl Acad Sci U S A.2016 Sep 6;113(36):E5271-80. |
PK11000 bound to and stabilized p53 DBD.Proc Natl Acad Sci U S A.2016 Sep 6;113(36):E5271-80. |
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