"目录号: HY-13734

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PX-12(IV-2)是可逆的硫氧还蛋白-1（Trx-1）抑制剂; 抑制MCF-7 和HT-29 cells细胞生长的IC50值分别为1.9和2.9 μM。

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生物活性

Description

PX-12(IV-2) is an irreversible inhibitor of Thioredoxin-1 (Trx-1); inhibits the growth of MCF-7 and HT-29 cells withIC50values of 1.9 and 2.9 μM, respectively.

IC50& Target

IC50: 1.9 (MCF-7), 2.9 μM (HT-29 cells)[1]

In Vitro

PX-12 inhibits the growth of MCF-7 and HT-29 cells with IC50values of 1.9 and 2.9 μM, respectively[1]. PX-12 particularly reduces the activity of Trx-1 by means of thio-alkylating critical cysteine residue (Cys73) which is located in the outside the conserved redox catalytic site of Trx-1. PX-12 affects the oxidation state of thiols in a number of cell surface proteins. Key surface receptors for platelet adhesion and activation are affected, including the collagen receptor GPVI and the von Willebrand factor receptor, GPIb. PX-12 inhibits thrombus formation over Type I collagen in whole blood under flow conditions[2]. Thioredoxin-1 (Trx-1) is a cellular redox protein that promotes tumor growth, inhibits apoptosis, and up-regulates hypoxia-inducible factor-1α and vascular endothelial growth factor[3]. PX-12 inhibits the growth of colorectal cancer DLD-1 and SW620 cells in a dose- and time-dependent manner. PX-12 reduces cell colony formation and induced a G2/M phase arrest of the cell cycle. PX-12 treatment induces apoptosis. PX-12 inhibits colorectal cancer cell migration and invasion. Treatment of cancer cells with PX-12 reduces NOX1, CDH17 and S100A4 mRNA expression, and increases KLF17 mRNA expression. PX-12 decreases S100A4 protein expression in the colorectal cancer cells[4].

In Vivo

PX-12 has been shown to havein vivoantitumor activity against human tumor xenografts including HT-29 colon cancer in SCID mice and has been tested in a phase I clinical trial in patients[3].

Clinical Trial

NCT00736372

Cascadian Therapeutics Inc.

Metastatic Cancer-Advanced Cancer

June 2008

Phase 1

NCT00417287

Cascadian Therapeutics Inc.-National Cancer Institute (NCI)-Translational Genomics Research Institute

Pancreatic Neoplasms

December 2006

Phase 2

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References

[1].Welsh SJ, et al. The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation. Mol Cancer Ther. 2003 Mar;2(3):235-43.

[2].Metcalfe C, et al. Thioredoxin Inhibitors Attenuate Platelet Function and Thrombus Formation.PLoS One. 2016 Oct 7;11(10):e0163006.

[3].Ramanathan RK, et al. A Phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors. Clin Cancer Res. 2007 Apr 1;13(7):2109-14.

[4].Wang F, et al. Thioredoxin-1 inhibitor, 1-methylpropyl 2-imidazolyl disulfide, inhibits the growth, migration and invasion of colorectal cancer cell lines. Oncol Rep. 2015 Feb;33(2):967-73.

[5].Lou M, et al. Physical interaction between human ribonucleotide reductase large subunit and thioredoxin increases colorectal cancer malignancy. J Biol Chem. 2017 Jun 2;292(22):9136-9149.