OXI-4503

Identification

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Name
OXI-4503
Accession Number
DB05143
Type
Small Molecule
Groups
Investigational
Description

OXI-4503 is investigated in clinical trials for treating cancer/tumors. OXI-4503 is a solid. OXI-4503 blocks and destroys tumor vasculature, resulting in extensive tumor cell death and necrosis. OXI-4503 (combretastatin A1 di-phosphate / CA1P) is a unique and highly potent, dual-mechanism vascular disrupting agent (VDA). In addition, however, preclinical data demonstrates that OXI-4503 is metabolized by oxidative enzymes (e.g., tyrosinase and peroxidases), which are elevated in many solid tumors and tumor infiltrates, to an orthoquinone chemical species that has direct cytotoxic effects on tumor cells. Preclinical studies have demonstrated that OXI-4503 has (i) single-agent activity against a range of xenograft tumor models; and (ii) synergistic or additive effects when incorporated in various combination regimens with chemotherapy, molecularly-targeted therapies (including tumor-angiogenesis inhibitors), and radiation therapy.

Structure
Thumb
Synonyms
  • CA1P
  • Combretastatin A-1 bis(phosphate)
  • Combretastatin A1 diphosphate
  • OXI4503
Product Ingredients
IngredientUNIICASInChI Key
OXI-4503 dipotassiumQ9F7QEH36F1014615-46-3IQYUGENRXZHYER-XNOMRPDFSA-L
Categories
UNII
JH6Z94GLUD
CAS number
288847-35-8
Weight
Average: 492.31
Monoisotopic: 492.058650144
Chemical Formula
C18H22O12P2
InChI Key
GSOXMQLWUDQTNT-WAYWQWQTSA-N
InChI
InChI=1S/C18H22O12P2/c1-25-13-8-7-12(16(29-31(19,20)21)18(13)30-32(22,23)24)6-5-11-9-14(26-2)17(28-4)15(10-11)27-3/h5-10H,1-4H3,(H2,19,20,21)(H2,22,23,24)/b6-5-
IUPAC Name
[3-methoxy-2-(phosphonooxy)-6-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenoxy]phosphonic acid
SMILES
[H]\C(=C(/[H])C1=C(OP(O)(O)=O)C(OP(O)(O)=O)=C(OC)C=C1)C1=CC(OC)=C(OC)C(OC)=C1

Pharmacology

Indication

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

Pharmacodynamics

OXi4503 blocks and destroys tumor vasculature, resulting in extensive tumor cell death and necrosis. In addition, however, preclinical data demonstrates that OXi4503 is metabolized by oxidative enzymes (e.g., tyrosinase and peroxidases), which are elevated in many solid tumors and tumor infiltrates, to an orthoquinone chemical species that has direct cytotoxic effects on tumor cells.

Mechanism of action

OXi4503 blocks and destroys tumor vasculature, resulting in extensive tumor cell death and necrosis. It induced the shutdown of tumor blood vessels and affected peripheral tumor regions less than central regions.

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
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
DrugInteraction
AluminiumAluminium can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminium acetoacetateAluminium acetoacetate can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminium glycinateAluminium glycinate can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Aluminum hydroxideAluminum hydroxide can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
CalciumCalcium can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium acetateCalcium acetate can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium CarbonateCalcium Carbonate can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium cationCalcium cation can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium ChlorideCalcium Chloride can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Calcium CitrateCalcium Citrate can cause a decrease in the absorption of OXI-4503 resulting in a reduced serum concentration and potentially a decrease in efficacy.
Additional Data Available
  • Extended Description
    Extended Description

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Evidence Level

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

References

General References
  1. Chan LS, Malcontenti-Wilson C, Muralidharan V, Christophi C: Alterations in vascular architecture and permeability following OXi4503 treatment. Anticancer Drugs. 2008 Jan;19(1):17-22. [PubMed:18043126]
  2. Hokland SL, Horsman MR: The new vascular disrupting agent combretastatin-A1-disodium-phosphate (OXi4503) enhances tumour response to mild hyperthermia and thermoradiosensitization. Int J Hyperthermia. 2007 Nov;23(7):599-606. [PubMed:18038290]
  3. Chan LS, Malcontenti-Wilson C, Muralidharan V, Christophi C: Effect of vascular targeting agent Oxi4503 on tumor cell kinetics in a mouse model of colorectal liver metastasis. Anticancer Res. 2007 Jul-Aug;27(4B):2317-23. [PubMed:17695520]
  4. Salmon HW, Siemann DW: Effect of the second-generation vascular disrupting agent OXi4503 on tumor vascularity. Clin Cancer Res. 2006 Jul 1;12(13):4090-4. [PubMed:16818709]
External Links
PubChem Compound
6918546
PubChem Substance
175426952
ChemSpider
5293743
BindingDB
50236033
ChEMBL
CHEMBL1205402

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentNeoplasms Metastasis1
1CompletedTreatmentTumors, Solid1
1TerminatedTreatmentLeukemia, Myelogenous, Acute / Myelodysplastic Syndromes1
1, 2RecruitingTreatmentAcute Myelogenous Leukaemia (AML) / Myelodysplastic Syndromes1

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 Solubility0.0268 mg/mLALOGPS
logP1.76ALOGPS
logP1.77ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)1.31ChemAxon
pKa (Strongest Basic)-4.3ChemAxon
Physiological Charge-4ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area170.44 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity113.07 m3·mol-1ChemAxon
Polarizability43.31 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8178
Blood Brain Barrier+0.9392
Caco-2 permeable+0.5621
P-glycoprotein substrateNon-substrate0.6563
P-glycoprotein inhibitor IInhibitor0.5894
P-glycoprotein inhibitor IINon-inhibitor0.7451
Renal organic cation transporterNon-inhibitor0.9072
CYP450 2C9 substrateNon-substrate0.7647
CYP450 2D6 substrateNon-substrate0.7938
CYP450 3A4 substrateSubstrate0.5659
CYP450 1A2 substrateInhibitor0.5726
CYP450 2C9 inhibitorNon-inhibitor0.7198
CYP450 2D6 inhibitorNon-inhibitor0.9068
CYP450 2C19 inhibitorInhibitor0.5589
CYP450 3A4 inhibitorInhibitor0.505
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6137
Ames testNon AMES toxic0.8531
CarcinogenicityNon-carcinogens0.6756
BiodegradationNot ready biodegradable0.7566
Rat acute toxicity2.6950 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7806
hERG inhibition (predictor II)Non-inhibitor0.8709
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 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 stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Stilbenes
Sub Class
Not Available
Direct Parent
Stilbenes
Alternative Parents
Phenyl phosphates / Styrenes / Phenoxy compounds / Methoxybenzenes / Anisoles / Alkyl aryl ethers / Organic oxides / Hydrocarbon derivatives
Substituents
Stilbene / Phenyl phosphate / Aryl phosphate / Aryl phosphomonoester / Phenoxy compound / Anisole / Phenol ether / Methoxybenzene / Styrene / Alkyl aryl ether
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Drug created on October 21, 2007 16:23 / Updated on March 11, 2019 19:38