Identification

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Name
PX-12
Accession Number
DB05448
Type
Small Molecule
Groups
Investigational
Description

PX-12 (1-methylpropyl 2-imidazolyl disulfide) is a small-molecule inhibitor of Trx-1 (thioredoxin-1), 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, PX-12 is indicated as a potential cancer treatment in combination with chemotherapy for patients with advanced metastatic cancer. Initial trials correlated doses of Px-12 with increased patient survival.

Structure
Thumb
Synonyms
  • 1-Methylpropyl-2-imidazolyl disulfide
External IDs
PX 12 / PX-12
Categories
UNII
8PQ9CZ8BTJ
CAS number
141400-58-0
Weight
Average: 188.314
Monoisotopic: 188.044189774
Chemical Formula
C7H12N2S2
InChI Key
BPBPYQWMFCTCNG-UHFFFAOYSA-N
InChI
InChI=1S/C7H12N2S2/c1-3-6(2)10-11-7-8-4-5-9-7/h4-6H,3H2,1-2H3,(H,8,9)
IUPAC Name
2-(butan-2-yldisulfanyl)-1H-imidazole
SMILES
CCC(C)SSC1=NC=CN1

Pharmacology

Indication

Investigated for use/treatment in cancer/tumors (unspecified), gastric cancer, and pancreatic cancer.

Pharmacodynamics

PX-12 is a small molecule irreversible inhibitor of the redox protein thioredoxin. Thioredoxin is involved in the first unique step in DNA synthesis. Thioredoxin also provides control over a number of transcription factors affecting cell proliferation and death through the mechanism of redox regulation Trx regulates cell growth through the following steps: 1) Trx is reduced into its active state, Trx (red) by the enzyme thioredoxin reductase. 2) Trx enters the nucleus to regulate transcription factor activity (factors which affect DNA replication). 3) Trx is excreted out of cell where it works with other growth factors (GF) to stimulate cell growth.

It has been shown that many cancer cells secrete thioredoxin; increased levels of thioredoxin protein have been reported in a wide range of human cancers including hepatoma, lung, squamous cervical carcinoma, primary gastric cancers, and colorectal carcinomas;thioredoxin stimulates the growth of a wide variety of human leukemia and solid tumor cell lines; thioredoxin, when it is over-produced, transforms normal cells into cancer cells; thioredoxin is a potent inhibitor of apoptosis and provides a survival as well as a growth advantage to tumors; elevated tumor thioredoxin levels have been associated with decreased patient survival in colon cancer and NSCLC; and elevated thioredoxin levels cause a decrease in sensitivity of cells to cancer drugs such as doxorubicin (14 fold), vincristine (8 fold), cisplatin (5 fold), and cytosine arabinoside (13 fold). Therefore PX-12, by limiting the over-expression of thioredoxin in human tumors, could reduce resistance to chemotherapy.

Mechanism of action

PX-12 irreversibly inhibits the redox protein thioredoxin, which has been associated with cancer and tumor growth.

TargetActionsOrganism
UThioredoxin reductase 1, cytoplasmicNot AvailableHumans
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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Absorption

the optimum PD dose was identified as 96 mg/m2 as a 3-hr infusion

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

Doses of PX-12 up to 226 mg/m2 were shown to be well tolerated and had minimal toxicity

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Jordan BF, Runquist M, Raghunand N, Gillies RJ, Tate WR, Powis G, Baker AF: 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. Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):529-36. [PubMed:15701837]
  2. Bayes M, Rabasseda X, Prous JR: Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Jun;29(5):359-73. [PubMed:17805439]
  3. Ramanathan RK, Kirkpatrick DL, Belani CP, Friedland D, Green SB, Chow HH, Cordova CA, Stratton SP, Sharlow ER, Baker A, Dragovich T: 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. [PubMed:17404093]
  4. Galmarini CM: Drug evaluation: the thioredoxin inhibitor PX-12 in the treatment of cancer. Curr Opin Investig Drugs. 2006 Dec;7(12):1108-15. [PubMed:17209529]
  5. Kiviharju K, Moilanen U, Leisola M, Eerikainen T: A chemostat study of Streptomyces peucetius var. caesius N47. Appl Microbiol Biotechnol. 2007 Jan;73(6):1267-74. Epub 2006 Nov 7. [PubMed:17115210]
  6. Baker AF, Dragovich T, Tate WR, Ramanathan RK, Roe D, Hsu CH, Kirkpatrick DL, Powis G: The antitumor thioredoxin-1 inhibitor PX-12 (1-methylpropyl 2-imidazolyl disulfide) decreases thioredoxin-1 and VEGF levels in cancer patient plasma. J Lab Clin Med. 2006 Feb;147(2):83-90. [PubMed:16459166]
  7. Bayes M, Rabasseda X, Prous JR: Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2004 Apr;26(3):211-44. [PubMed:15148527]
  8. Bergink AP, van Meurs JB, Loughlin J, Arp PP, Fang Y, Hofman A, van Leeuwen JP, van Duijn CM, Uitterlinden AG, Pols HA: Estrogen receptor alpha gene haplotype is associated with radiographic osteoarthritis of the knee in elderly men and women. Arthritis Rheum. 2003 Jul;48(7):1913-22. [PubMed:12847685]
  9. Welsh SJ, Williams RR, Birmingham A, Newman DJ, Kirkpatrick DL, Powis G: 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. [PubMed:12657718]
  10. Husbeck B, Powis G: 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. Carcinogenesis. 2002 Oct;23(10):1625-30. [PubMed:12376470]
External Links
PubChem Compound
219104
PubChem Substance
175427007
ChemSpider
189920
BindingDB
50426071
ChEBI
94291
ChEMBL
CHEMBL406050

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentCancer, Advanced / Metastatic Cancers1
2TerminatedTreatmentNeoplasms, Pancreatic1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.783 mg/mLALOGPS
logP2.78ALOGPS
logP2.77ChemAxon
logS-2.4ALOGPS
pKa (Strongest Acidic)10.93ChemAxon
pKa (Strongest Basic)4.81ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area28.68 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity50.87 m3·mol-1ChemAxon
Polarizability19.94 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9902
Blood Brain Barrier+0.9787
Caco-2 permeable-0.5509
P-glycoprotein substrateNon-substrate0.705
P-glycoprotein inhibitor INon-inhibitor0.8048
P-glycoprotein inhibitor IINon-inhibitor0.9729
Renal organic cation transporterNon-inhibitor0.8732
CYP450 2C9 substrateNon-substrate0.8833
CYP450 2D6 substrateNon-substrate0.8485
CYP450 3A4 substrateNon-substrate0.7991
CYP450 1A2 substrateInhibitor0.6477
CYP450 2C9 inhibitorNon-inhibitor0.5988
CYP450 2D6 inhibitorNon-inhibitor0.7987
CYP450 2C19 inhibitorInhibitor0.6645
CYP450 3A4 inhibitorNon-inhibitor0.8573
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6013
Ames testNon AMES toxic0.6507
CarcinogenicityNon-carcinogens0.8237
BiodegradationNot ready biodegradable0.866
Rat acute toxicity2.1935 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9439
hERG inhibition (predictor II)Non-inhibitor0.9451
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as imidazoles. These are compounds containing an imidazole ring, which is an aromatic five-member ring with two nitrogen atoms at positions 1 and 3, and three carbon atoms.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azoles
Sub Class
Imidazoles
Direct Parent
Imidazoles
Alternative Parents
Heteroaromatic compounds / Organic disulfides / Sulfenyl compounds / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Hydrocarbon derivatives
Substituents
Heteroaromatic compound / Imidazole / Organic disulfide / Azacycle / Sulfenyl compound / Organic nitrogen compound / Organopnictogen compound / Hydrocarbon derivative / Organosulfur compound / Organonitrogen compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Thioredoxin-disulfide reductase activity
Specific Function
Isoform 1 may possess glutaredoxin activity as well as thioredoxin reductase activity and induces actin and tubulin polymerization, leading to formation of cell membrane protrusions. Isoform 4 enha...
Gene Name
TXNRD1
Uniprot ID
Q16881
Uniprot Name
Thioredoxin reductase 1, cytoplasmic
Molecular Weight
70905.58 Da
References
  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235]

Drug created on November 18, 2007 11:25 / Updated on February 21, 2019 09:31