PK11007
目录号 : GC32946
PK11000 stabilizes the DBD of both WT and mutant p53 proteins by covalent cysteine modification without compromising DNA binding and effective in inducing cell death.
Cas No.:38275-34-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
PK11000 stabilizes the DBD of both WT and mutant p53 proteins by covalent cysteine modification without compromising DNA binding and effective in inducing cell death.
[1] Bauer MR, et al. Proc Natl Acad Sci U S A. 2016, 113(36):E5271-80.
| Cas No. | 38275-34-2 | SDF | |
| Canonical SMILES | O=C(C1=NC(S(=O)(C)=O)=NC=C1Cl)O | ||
| 分子式 | C6H5ClN2O4S | 分子量 | 236.63 |
| 溶解度 | DMSO : 100 mg/mL (422.60 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.226 mL | 21.13 mL | 42.2601 mL |
| 5 mM | 0.8452 mL | 4.226 mL | 8.452 mL |
| 10 mM | 0.4226 mL | 2.113 mL | 4.226 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Mutant p53 as a target for cancer treatment
Eur J Cancer 2017 Sep;83:258-265.PMID:28756138DOI:10.1016/j.ejca.2017.06.023.
TP53 (p53) is the single most frequently altered gene in human cancers, with mutations being present in approximately 50% of all invasive tumours. However, in some of the most difficult-to-treat cancers such as high-grade serous ovarian cancers, triple-negative breast cancers, oesophageal cancers, small-cell lung cancers and squamous cell lung cancers, p53 is mutated in at least 80% of samples. Clearly, therefore, mutant p53 protein is an important candidate target against which new anticancer treatments could be developed. Although traditionally regarded as undruggable, several compounds such as p53 reactivation and induction of massive apoptosis-1 (PRIMA-1), a methylated derivative and structural analogue of PRIMA-1, i.e. APR-246, 2-sulfonylpyrimidines such as PK11007, pyrazoles such as PK7088, zinc metallochaperone-1 (ZMC1), a third generation thiosemicarbazone developed by Critical Outcome Techonologies Inc. (COTI-2) as well as specific peptides have recently been reported to reactive mutant p53 protein by converting it to a form exhibiting wild-type properties. Consistent with the reactivation of mutant p53, these compounds have been shown to exhibit anticancer activity in preclinical models expressing mutant p53. To date, two of these compounds, i.e. APR-246 and COTI-2 have progressed to clinical trials. A phase I/IIa clinical trial with APR-246 reported no major adverse effect. Currently, APR-246 is undergoing a phase Ib/II trial in patients with advanced serous ovarian cancer, while COTI-2 is being evaluated in a phase I trial in patients with advanced gynaecological cancers. It remains to be shown however, whether any mutant p53 reactivating compound has efficacy for the treatment of human cancer.
Mutant p53 in breast cancer: potential as a therapeutic target and biomarker
Breast Cancer Res Treat 2018 Jul;170(2):213-219.PMID:29564741DOI:10.1007/s10549-018-4753-7.
Objective: The aim of this article is to discuss mutant p53 as a possible therapeutic target and biomarker for breast cancer. Results: TP53 (p53) is the most frequently mutated gene in invasive breast cancer. Although mutated in 30-35% of all cases, p53 is mutated in approximately 80% of triple-negative (TN) tumors (i.e., tumors negative for ER, PR, and HER2). Because of this high prevalence, mutated p53 is both a potential biomarker and therapeutic target for patients with breast cancer, especially for those with the TN subtype. Although several retrospective studies have investigated a potential prognostic and therapy predictive role for mutant p53 in breast cancer, the results to date are mixed. Thus, at present, mutant p53 cannot be recommended as a prognostic or therapy predictive biomarker in breast cancer. In contrast to the multiple reports on a potential biomarker role, few studies had until recently, investigated mutant p53 as a potential target for breast cancer treatment. In the last decade, however, several compounds have become available which can reactivate mutant p53 protein and convert it to a conformation with wild-type properties. Some of these compounds, especially PRIMA-1, APR-246 PK11007, and COTI-2, have been found to exhibit anticancer activity in preclinical models of breast cancer. Conclusion: Since p53 is mutated in the vast majority of TN breast cancers, compounds such as APR-246, PK11007, and COTI-2 are potential treatments for patients with this subform of the disease. Further research is necessary to identify a potential biomarker role for mutant p53 in breast cancer.
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.PMID:29069577DOI:10.1016/j.canlet.2017.09.053.
The identification of a targeted therapy for patients with triple-negative breast cancer (TNBC) is one of the most urgent needs in breast cancer therapeutics. The p53 gene is mutated in approximately 80% of patients with TNBC, and is a potential therapeutic target for patients with this form of breast cancer. The 2-sulfonylpyrimidine compound, PK11007, preferentially decreases viability in p53-compromised cancer cell lines. We investigated PK11007 as a potential new treatment for TNBC. IC50 values for inhibition of proliferation in a panel of 17 breast cell lines by PK11007 ranged from 2.3 to 42.2 μM. There were significantly lower IC50 values for TNBC than for non-TNBC cell lines (p = 0.03) and for p53-mutated cell lines compared with p53 WT cells (p = 0.003). Response to PK11007 however, was independent of the estrogen receptor (ER) or HER2 status of the cell lines. In addition to inhibiting cell proliferation, PK11007 induced apoptosis in p53 mutant cell lines. Using RNAseq and gene ontology analysis, we found that PK11007 altered the expression of genes enriched in pathways involved in regulated cell death, regulation of apoptosis, signal transduction, protein refolding and locomotion. The observations that PK11007 inhibited cell proliferation, induced apoptosis and altered genes involved in cell death are all consistent with the ability of PK11007 to reactivate mutant p53. Based on our data, we conclude that targeting mutant p53 with PK11007 is a potential approach for treating p53-mutated breast cancer, including the subgroup with TN disease.
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.PMID:27551077DOI:10.1073/pnas.1610421113.
The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53's oncogenic mutants are just destabilized and rapidly aggregate, and are targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity in several cell lines, especially those with mutationally compromised 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.