This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

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Name
PX-478
Accession Number
DB06082
Type
Small Molecule
Groups
Investigational
Description

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.

Structure
Thumb
Synonyms
Not Available
Categories
UNII
T23U22X160
CAS number
685898-44-6
Weight
Average: 394.11
Monoisotopic: 392.0228033
Chemical Formula
C13H20Cl4N2O3
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

Pharmacology

Indication

Investigated for use/treatment in cancer/tumors (unspecified).

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).

TargetActionsOrganism
UHypoxia-inducible factor 1-alphaNot AvailableHumans
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
Toxicity
Not Available
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. 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. [PubMed:18202012]
  2. 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. [PubMed:16206237]
  3. 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. [PubMed:15967100]
External Links
ChemSpider
9409841
ChEMBL
CHEMBL4061538

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAdvanced Solid Tumors / Malignant Lymphomas1

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 Solubility0.017 mg/mLALOGPS
logP-0.34ALOGPS
logP-3.3ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)1.54ChemAxon
pKa (Strongest Basic)9.42ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area86.38 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity89.17 m3·mol-1ChemAxon
Polarizability31.67 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

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
Phenylalanine or derivatives / 3-phenylpropanoic-acid / Alpha-amino acid / Amphetamine or derivatives / L-alpha-amino acid / Nitrogen mustard / Aralkylamine / Monocyclic benzene moiety / Benzenoid / Amino acid
show 22 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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

Drug created on November 18, 2007 11:29 / Updated on June 04, 2019 06:21