PX-12
Identification
- Generic Name
- PX-12
- DrugBank Accession Number
- DB05448
- Background
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.
- Type
- Small Molecule
- Groups
- Investigational
- Structure
- Weight
- Average: 188.314
Monoisotopic: 188.044189774 - Chemical Formula
- C7H12N2S2
- Synonyms
- 1-Methylpropyl-2-imidazolyl disulfide
- External IDs
- PX 12
- PX-12
Pharmacology
- Indication
Investigated for use/treatment in cancer/tumors (unspecified), gastric cancer, and pancreatic cancer.
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- 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.
Target Actions Organism UThioredoxin reductase 1, cytoplasmic Not Available Humans - 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
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
Doses of PX-12 up to 226 mg/m2 were shown to be well tolerated and had minimal toxicity
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Not Available
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- 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
- Aromatic heteromonocyclic compound / Azacycle / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / Organic disulfide / Organic nitrogen compound / Organonitrogen compound / Organopnictogen compound / Organosulfur compound
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 8PQ9CZ8BTJ
- CAS number
- 141400-58-0
- 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
References
- General References
- 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. [Article]
- Bayes M, Rabasseda X, Prous JR: Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Jun;29(5):359-73. [Article]
- 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. [Article]
- Galmarini CM: Drug evaluation: the thioredoxin inhibitor PX-12 in the treatment of cancer. Curr Opin Investig Drugs. 2006 Dec;7(12):1108-15. [Article]
- 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. [Article]
- 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. [Article]
- Bayes M, Rabasseda X, Prous JR: Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2004 Apr;26(3):211-44. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- External Links
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 2 Terminated Treatment Pancreatic Neoplasms 1 1 Completed Treatment Advanced Malignant Neoplasm / Metastatic Cancer 1
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
Property Value Source Water Solubility 0.783 mg/mL ALOGPS logP 2.78 ALOGPS logP 2.77 Chemaxon logS -2.4 ALOGPS pKa (Strongest Acidic) 10.93 Chemaxon pKa (Strongest Basic) 4.81 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 1 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 28.68 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 50.87 m3·mol-1 Chemaxon Polarizability 19.94 Å3 Chemaxon Number of Rings 1 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule Yes Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9902 Blood Brain Barrier + 0.9787 Caco-2 permeable - 0.5509 P-glycoprotein substrate Non-substrate 0.705 P-glycoprotein inhibitor I Non-inhibitor 0.8048 P-glycoprotein inhibitor II Non-inhibitor 0.9729 Renal organic cation transporter Non-inhibitor 0.8732 CYP450 2C9 substrate Non-substrate 0.8833 CYP450 2D6 substrate Non-substrate 0.8485 CYP450 3A4 substrate Non-substrate 0.7991 CYP450 1A2 substrate Inhibitor 0.6477 CYP450 2C9 inhibitor Non-inhibitor 0.5988 CYP450 2D6 inhibitor Non-inhibitor 0.7987 CYP450 2C19 inhibitor Inhibitor 0.6645 CYP450 3A4 inhibitor Non-inhibitor 0.8573 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6013 Ames test Non AMES toxic 0.6507 Carcinogenicity Non-carcinogens 0.8237 Biodegradation Not ready biodegradable 0.866 Rat acute toxicity 2.1935 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9439 hERG inhibition (predictor II) Non-inhibitor 0.9451
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-054k-9300000000-68939fcd9308e9863626 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0019-9500000000-8dbb43d67ccac2fd6f58 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-053r-9800000000-a8fc3f9b7bed4bfe9cec Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0a4i-9000000000-cfbeb64d0ab9fe90ebd2 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0a4j-9000000000-b9b4fcf21cc88e487df2 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-052f-9000000000-d6f74e0ae7e7765bcb09 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-000t-9200000000-8c004e3c0eb51a122b20 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 138.78711 predictedDeepCCS 1.0 (2019) [M+H]+ 142.28064 predictedDeepCCS 1.0 (2019) [M+Na]+ 151.77519 predictedDeepCCS 1.0 (2019)
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
- 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. [Article]
Drug created at November 18, 2007 18:25 / Updated at June 12, 2020 16:52