PX-12

Investigational

Details

Stereochemistry	RACEMIC
Molecular Formula	C7H12N2S2
Molecular Weight	188.314
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCC(C)SSC1=NC=CN1

InChI

InChIKey=BPBPYQWMFCTCNG-UHFFFAOYSA-N

InChI=1S/C7H12N2S2/c1-3-6(2)10-11-7-8-4-5-9-7/h4-6H,3H2,1-2H3,(H,8,9)

HIDE SMILES / InChI

Description
Sources: https://www.drugbank.ca/drugs/DB05448
Curator's Comment: The description was created based on several sources, including https://clinicaltrials.gov/ct2/show/NCT00417287 | https://www.ncbi.nlm.nih.gov/pubmed/23327656 | https://clinicaltrials.gov/ct2/show/NCT00736372 | https://www.ncbi.nlm.nih.gov/pubmed/24172913

DB05448 (PX-12, 1-methyl propyl 2-imidazolyl disulfide) is a small molecule irreversible inhibitor of the redox protein thioredoxin, which has been associated with cancer and tumor growth. DB05448 stimulates apoptosis, down-regulates HIF-1α and vascular endothelial growth factor (VEGF) and inhibits tumor growth in animal models. Since high levels of Trx-1 have been associated with colorectal, gastric and lung cancers, DB05448 is indicated as a potential cancer treatment in combination with chemotherapy for patients with advanced metastatic cancer. Initial trials correlated doses of DB05448 with increased patient survival.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Thioredoxin 2 Target ID: CHEMBL2010624 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23327656	Inhibitor 8297		2.11 µM [IC50]
Thioredoxin reductase 1, cytoplasmic 3 Target ID: Q16881\|\|\|Q6VB41\|\|\|Q6YNQ1 Gene ID: 7296.0 Gene Symbol: TXNRD1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/12657718 \| https://www.ncbi.nlm.nih.gov/pubmed/9605422	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pancreatic cancer 97 Sources: https://clinicaltrials.gov/ct2/show/NCT00417287	Primary		Phase II 1132	Unknown Approved Use Unknown
Metastatic cancer 1 Sources: https://clinicaltrials.gov/ct2/show/NCT00736372	Primary		Phase I 428	Unknown Approved Use Unknown

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 CYP1B1 19

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=174006855	inconclusive [IC50 37.2212 uM]
CYP1B1 67	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/12376470/	yes

PubMed

Title	Date	PubMed
Thioredoxin expression in primary T-cell acute lymphoblastic leukemia and its therapeutic implication.	2001 Oct 1	11585774
Normal-phase and stability-indicating reversed-phase high-performance liquid chromatographic methods for the determination of the novel antitumor agent: 1-methylpropyl-2-imidazolyldisulfide.	2002 Mar 5	11888051
The thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth factor formation.	2003 Mar	12657718

Patents

Sample Use Guides

In Vivo Use Guide

3 hour intravenous infusion as a dose of either 54 mg/m2 or 128 mg/m2 daily for 5 days every three weeks.

Route of Administration: Intravenous

In Vitro Use Guide

Human lung cancer Calu-6 cells were used for activity evaluation. 1×10^4 cells per well were seeded in 96-well microtiter plates (Nunc). After incubation with the 1, 2, 3, 4 and 5 mkM of PX-12 (DB05448) for the 72 h, MTT solution [20 μl; 2 mg/ml in phosphate-buffered saline (PBS)] was added to each well of the 96-well plates. The plates were additionally incubated for 3 h at 37 °C. Medium was removed from the plates by pipetting, and 200 μl DMSO was added to each well to solubilize the formazan crystals. The optical density was measured at 570 nm using a microplate reader (Synergy™ 2, BioTek Instruments Inc., Winooski, VT, USA).

Name

Type

Language

PX-12

Common Name

English

1-METHYLPROPYL-2-IMIDAZOLYL DISULFIDE

Systematic Name

English

Code System Code Type Description

NCI_THESAURUS

C74082