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

Molecular Formula	C7H12N2S2
Molecular Weight	188.314
Charge	0
Count

Stereochemistry	RACEMIC
Additional Stereochemistry	No
Defined Stereocenters	0 / 1
E/Z Centers	0
Optical Activity	( + / - )

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
Enhancement of metabolic oxidative stress-induced cytotoxicity by the thioredoxin inhibitor 1-methylpropyl 2-imidazolyl disulfide is mediated through the ASK1-SEK1-JNK1 pathway.	2002 Dec	12435809
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 redox protein thioredoxin-1 regulates the constitutive and inducible expression of the estrogen metabolizing cytochromes P450 1B1 and 1A1 in MCF-7 human breast cancer cells.	2002 Oct	12376470
Estrogen receptor alpha gene haplotype is associated with radiographic osteoarthritis of the knee in elderly men and women.	2003 Jul	12847685
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
Gateways to clinical trials.	2004 Apr	15148527
The thioredoxin-1 inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) decreases vascular permeability in tumor xenografts monitored by dynamic contrast enhanced magnetic resonance imaging.	2005 Jan 15	15701837
Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study.	2005 Jan 31	15655539
Drug evaluation: the thioredoxin inhibitor PX-12 in the treatment of cancer.	2006 Dec	17209529
A Phase I pharmacokinetic and pharmacodynamic study of PX-12, a novel inhibitor of thioredoxin-1, in patients with advanced solid tumors.	2007 Apr 1	17404093
A chemostat study of Streptomyces peucetius var. caesius N47.	2007 Jan	17115210
Gateways to clinical trials.	2007 Jun	17805439
2-[(1-methylpropyl)dithio]-1H-imidazole inhibits tubulin polymerization through cysteine oxidation.	2008 Jan	18202017
Macrophage migration inhibitory factor activates hypoxia-inducible factor in a p53-dependent manner.	2008 May 21	18493321

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).

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:48:26 UTC 2023` Edited by `admin` on `Fri Dec 15 15:48:26 UTC 2023`
Record UNII	8PQ9CZ8BTJ
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PX-12

Common Name

English

1-METHYLPROPYL-2-IMIDAZOLYL DISULFIDE

Systematic Name

English

Code System Code Type Description

NCI_THESAURUS

C74082