874146-69-7|5-Chloro-2-((4-fluorobenzyl)sulfonyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidine-4-carboxamide|CsnPharm

CAS No.: 874146-69-7

PK11007 Catalog No. CSN25246

Synonyms: PK11007

PK11007 is mild thiol alkylator with anticancer activity in several cell lines, especially those with mutationally compromised p53.

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实验方案

技术信息

生物活性

描述The tumor suppressor p53 is a key mediator in cell cycle arrest, DNA repair, and apoptosis. PK11007 is a mild thiol alkylator that shows anticancer activity towards p53-compromised cell lines. Incubation of stabilized full-length p53 with 1mM PK11007 for 2 h did not affect the binding of p53-GADD45a and the K_d value was 33.7nM. Treatment with PK11007 at 15-30µM markedly reduced cell viability in mutant p53 cell lines MKN1 (V143A), HUH-7 (Y220C), NUGC-3 (Y220C), and SW480 (R273H/P309S). PK11007 reduced cell viability of p53 WT cancer cell lines (HUH-6 and NUGC-4) and fibroblast cell line WI-38 only at high concentrations (60 and 120µM). The downregulation of p53 protein expression by siRNA did not alter PK11007-mediated viability reduction in HUH-6 and HUH-7 cells. In MKN1 cells (p53-V143A), PK11007 at 15 and 20µM resulted in a significant viability difference between wild-type and p53^-/- cells. The protein levels of p53 target genes, including p21, MDM2, and PUMA, were upregulated by PK11007 (15, 30, and 60µM) in NUGC-3 (p53-Y220C), HUH-7 (p53-Y220C), and MKN1 (p53-V143A) cells. PK11007 (15, 30, and 60µM) also dose-dependently upregulated the protein level of spliced XBP-1, a key marker for the activation of unfolded protein response, in HUH-7 cells^[1]. PK11007 inhibited the proliferation of a panel of 17 breast cell lines with IC50 values varied from 2.3 to 42.2μM^[2].
作用机制The alkylation of the surface-exposed redox-sensitive cysteines (i.e. C182 and C277) by PK11007 stabilizes the DNA-binding domain of p53 in vitro without compromising its DNA-binding affinity^[1].
参考文献

[1] Bauer MR, Joerger AC, Fersht AR. 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells. Proc Natl Acad Sci U S A. 2016;113(36):E5271-E5280. doi:10.1073/pnas.1610421113
[2] Synnott NC, Bauer MR, Madden S, 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;414:99-106. doi:10.1016/j.canlet.2017.09.053

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.3372 mL
- 11.6860 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

技术信息

CAS号

874146-69-7

储存条件

粉末: Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C15H11ClFN5O3S2

运输

蓝冰

分子量

427.86

别名

PK11007

溶解度

DMSO	240.0 mg/mL (560.9 mM) warming

动物实验配方

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