PX-478
Identification
- Generic Name
- PX-478
- DrugBank Accession Number
- DB06082
- Background
PX-478 is a small molecule inhibitor of hypoxia inducible factor (HIF)-1 alpha currently in a clinical trial in patients with advanced metastatic cancer and lymphoma. PX-478 was effective in models of both non-small cell lung cancer and small cell lung cancer that express HIF-1 alpha.
- Type
- Small Molecule
- Groups
- Investigational
- Structure
- Weight
- Average: 394.11
Monoisotopic: 392.0228033 - Chemical Formula
- C13H20Cl4N2O3
- Synonyms
- Not Available
Pharmacology
- Indication
Investigated for use/treatment in cancer/tumors (unspecified).
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- Pharmacodynamics
Not Available
- Mechanism of action
PX-478 is a novel small molecule compound that inhibits the activity of hypoxia inducible factor (HIF)-1 alpha, a transcription factor that controls the expression of a number of genes important for growth and survival of cancer cells. Genes regulated by HIF-1 alpha contribute to diverse functions including new blood vessel growth (angiogenesis), use of glucose for energy, and protection against apoptosis (programmed cell death). Preclinical data have demonstrated that PX-478 can induce apoptosis in experimental tumor models, as well as the down-regulation of factors which control angiogenesis, such as vascular endothelial growth factor (VEGF).
Target Actions Organism UHypoxia-inducible factor 1-alpha inhibitorHumans - Absorption
Not Available
- 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
Not Available
- 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 phenylalanine and derivatives. These are compounds containing phenylalanine or a derivative thereof resulting from reaction of phenylalanine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Phenylalanine and derivatives
- Alternative Parents
- Phenylpropanoic acids / Amphetamines and derivatives / L-alpha-amino acids / Nitrogen mustard compounds / Aralkylamines / Amino acids / Trisubstituted amine oxides and derivatives / Monocarboxylic acids and derivatives / Carboxylic acids / Hydrochlorides show 7 more
- Substituents
- 3-phenylpropanoic-acid / Alkyl chloride / Alkyl halide / Alpha-amino acid / Amine / Amino acid / Amphetamine or derivatives / Aralkylamine / Aromatic homomonocyclic compound / Benzenoid show 22 more
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- T23U22X160
- CAS number
- 685898-44-6
- InChI Key
- GIGCDIVNDFQKRA-LTCKWSDVSA-N
- InChI
- InChI=1S/C13H18Cl2N2O3.2ClH/c14-5-7-17(20,8-6-15)11-3-1-10(2-4-11)9-12(16)13(18)19;;/h1-4,12H,5-9,16H2,(H,18,19);2*1H/t12-;;/m0../s1
- IUPAC Name
- N-{4-[(2S)-2-amino-2-carboxyethyl]phenyl}-2-chloro-N-(2-chloroethyl)ethanamine oxide dihydrochloride
- SMILES
- Cl.Cl.N[C@@H](CC1=CC=C(C=C1)[N+]([O-])(CCCl)CCCl)C(O)=O
References
- General References
- Koh MY, Spivak-Kroizman T, Venturini S, Welsh S, Williams RR, Kirkpatrick DL, Powis G: Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha. Mol Cancer Ther. 2008 Jan;7(1):90-100. doi: 10.1158/1535-7163.MCT-07-0463. [Article]
- Jordan BF, Black K, Robey IF, Runquist M, Powis G, Gillies RJ: Metabolite changes in HT-29 xenograft tumors following HIF-1alpha inhibition with PX-478 as studied by MR spectroscopy in vivo and ex vivo. NMR Biomed. 2005 Nov;18(7):430-9. [Article]
- Jordan BF, Runquist M, Raghunand N, Baker A, Williams R, Kirkpatrick L, Powis G, Gillies RJ: Dynamic contrast-enhanced and diffusion MRI show rapid and dramatic changes in tumor microenvironment in response to inhibition of HIF-1alpha using PX-478. Neoplasia. 2005 May;7(5):475-85. [Article]
- External Links
- ChemSpider
- 9409841
- BindingDB
- 50231387
- ChEMBL
- CHEMBL4061538
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 1 Completed Treatment Advanced Solid Tumors / Lymphoma 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 0.017 mg/mL ALOGPS logP -0.34 ALOGPS logP -3.3 Chemaxon logS -4.3 ALOGPS pKa (Strongest Acidic) 1.54 Chemaxon pKa (Strongest Basic) 9.42 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 86.38 Å2 Chemaxon Rotatable Bond Count 8 Chemaxon Refractivity 89.17 m3·mol-1 Chemaxon Polarizability 31.67 Å3 Chemaxon Number of Rings 1 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not Available
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 174.49881 predictedDeepCCS 1.0 (2019) [M+H]+ 176.89491 predictedDeepCCS 1.0 (2019) [M+Na]+ 182.80849 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Ubiquitin protein ligase binding
- Specific Function
- Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transp...
- Gene Name
- HIF1A
- Uniprot ID
- Q16665
- Uniprot Name
- Hypoxia-inducible factor 1-alpha
- Molecular Weight
- 92669.595 Da
References
- Schwartz DL, Bankson JA, Lemos R Jr, Lai SY, Thittai AK, He Y, Hostetter G, Demeure MJ, Von Hoff DD, Powis G: Radiosensitization and stromal imaging response correlates for the HIF-1 inhibitor PX-478 given with or without chemotherapy in pancreatic cancer. Mol Cancer Ther. 2010 Jul;9(7):2057-67. doi: 10.1158/1535-7163.MCT-09-0768. Epub 2010 Jun 29. [Article]
Drug created at November 18, 2007 18:29 / Updated at May 04, 2022 15:36