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

Identification

Generic Name
Methoxyamine
DrugBank Accession Number
DB06328
Background

Not Available

Type
Small Molecule
Groups
Investigational
Structure
Weight
Average: 47.057
Monoisotopic: 47.037113785
Chemical Formula
CH5NO
Synonyms
Not Available
External IDs
  • TRC102

Pharmacology

Indication

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

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action

Methoyxamine is investigated for use as an adjunct to alkylating agents, reverse resistance to chemotherapy, and enhancing radiation therapy.
Methoxyamine’s proposed mechanism of action is through blocking of the abasic sites (apurinic/apyrimidinic - AP sites) created by the cleavage of base excision repair (BER) glycoslyates. DNA alkylating agents cause cell death through excessive DNA damage by adduct formation. The human mechanism for DNA repair is very efficient and cancer therapeutics which use this mechanism are often ineffective due to resistance by efficient repair mechanisms such as base excision repair (BER). Alkylating agents such as tezmozolomide form methylated DNA adducts such as O6-methylguanine (O6mG), 7-methylguanine (N7mG) and 3-methyladenine (N3mA). O6mG is a cytotoxic and genotoxic adduct which is repaired by O6-methylguanine DNA-methyltransferase (MGMT). O6mG’s cytotoxicity is due to the mismatch repair mechanism (MMR), but cell induced defects in this repair pathway can lead to drug resistance. The N7mG (dominant lesions caused by methylating agents) and N3mA adducts are both repaired by the BER mechanism. Methoxyamine disrupts the BER pathway, increasing the amount of cytotoxic adducts, which results in cell death. Methoxyamine inhibits BER by stabilizing the AP sites created by cleavage of BER glysosylates, forming MX-AP lesions.

Methoxyamine may be an effective adjunct to iododeoxyuridine(IUdR) induced radiosensitization and radiation treatment. IUdR is a halogenated pyrimidine which is incorporated into cellular DNA instead of thymidine, which enhances radiotumor sensitivity. Methoxyamine is proposed to have a dual action in this treatment as it alters cell cycle kinetics as well as prevents repair of DNA by BER, allowing increased sensitivity of tumor cells to DNA damage by radiation therapy. The efficiency of cell cycle repair has been shown to be cell cycle dependent, with the G1 phase being second most sensitive to ionizing radiation (the mitotic, M, phase is the most sensitive). Methoxyamine increases the amount of protein 53 (P53) and protein Rb (pRB), senescence factors which cause the cell to remain in the G1 phase. Methoxyamine also creates a stringent checkpoint at the G1/S boundary as well as an insufficient checkpoint at the G2 stage, preventing cells from going into the S phase. The increased number of G1 cells makes methoxyamine treated tumors more susceptible to ionizing radiation.

The temozolomide and methoxyamine created lesion MX-AP not only disrupts the BER pathway but inhibits topoisomerase II alpha (topo II), an enzyme necessary for DNA replication, recombination and chromosome segregation. MX-AP sites block DNA replication and interfere with choromosome splitting. It is currently uncertain how what the interaction between topoisomerase II and methoxyamine causes cytotoxicity, but several mechanisms have been proposed, such as MX-AP sites binding to topo II, thus reducing their functionality by forming a toxic complex.

TargetActionsOrganism
UDNANot 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

Adverse Effects
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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

Products

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Product Ingredients
IngredientUNIICASInChI Key
Methoxyamine hydrochloride203546OLMF593-56-6XNXVOSBNFZWHBV-UHFFFAOYSA-N

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as organooxygen compounds. These are organic compounds containing a bond between a carbon atom and an oxygen atom.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Not Available
Direct Parent
Organooxygen compounds
Alternative Parents
Organic nitrogen compounds / Hydrocarbon derivatives
Substituents
Aliphatic acyclic compound / Hydrocarbon derivative / Organic nitrogen compound / Organooxygen compound
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
a small molecule (CPD-7648)
Affected organisms
Not Available

Chemical Identifiers

UNII
9TZH4WY30J
CAS number
67-62-9
InChI Key
GMPKIPWJBDOURN-UHFFFAOYSA-N
InChI
InChI=1S/CH5NO/c1-3-2/h2H2,1H3
IUPAC Name
O-methylhydroxylamine
SMILES
CON

References

General References
  1. Yan L, Bulgar A, Miao Y, Mahajan V, Donze JR, Gerson SL, Liu L: Combined treatment with temozolomide and methoxyamine: blocking apurininc/pyrimidinic site repair coupled with targeting topoisomerase IIalpha. Clin Cancer Res. 2007 Mar 1;13(5):1532-9. [Article]
  2. Yan T, Seo Y, Schupp JE, Zeng X, Desai AB, Kinsella TJ: Methoxyamine potentiates iododeoxyuridine-induced radiosensitization by altering cell cycle kinetics and enhancing senescence. Mol Cancer Ther. 2006 Apr;5(4):893-902. [Article]
  3. Liu L, Gerson SL: Therapeutic impact of methoxyamine: blocking repair of abasic sites in the base excision repair pathway. Curr Opin Investig Drugs. 2004 Jun;5(6):623-7. [Article]
ChemSpider
3970
ChEMBL
CHEMBL1213633
Wikipedia
Methoxyamine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2RecruitingTreatmentAdenocarcinoma of Lung (Disorder) / Lung Large Cell Carcinoma / Non-squamous Non-small-cell Lung Cancer (NSQ NSCLC) / Stage III Lung Cancer AJCC v8 / Stage IIIA Lung Cancer AJCC v8 / Stage IIIB Lung Cancer AJCC v8 / Stage IIIC Lung Cancer AJCC v81
2TerminatedTreatmentAdult Brain Glioblastoma1
1Active Not RecruitingTreatmentLocally Advanced Lung Non-Squamous Non-Small Cell Carcinoma / Stage III Lung Adenocarcinoma AJCC v7 / Stage III Lung Large Cell Carcinoma AJCC v7 / Stage III Non-Small Cell Lung Cancer AJCC v7 / Stage IIIA Lung Adenocarcinoma AJCC v7 / Stage IIIA Lung Large Cell Carcinoma AJCC v7 / Stage IIIA Non-Small Cell Lung Cancer AJCC v7 / Stage IIIB Lung Adenocarcinoma AJCC v7 / Stage IIIB Lung Large Cell Carcinoma AJCC v7 / Stage IIIB Non-Small Cell Lung Cancer AJCC v7 / Stage IV Lung Adenocarcinoma AJCC v7 / Stage IV Lung Large Cell Carcinoma AJCC v7 / Stage IV Non-Small Cell Lung Cancer AJCC v71
1CompletedTreatmentAdult Nasal Type Extranodal NK/T-Cell Lymphoma / Anaplastic Large Cell Lymphoma / Angioimmunoblastic T-cell Lymphoma (AITL) / Chronic Lymphocytic Leukemia (CLL) - Refractory / Cutaneous B-Cell Non-Hodgkin Lymphoma / Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue / Hepato-splenic T-cell Lymphoma / Intraocular Lymphoma / Nodal marginal zone B-cell lymphomas / Peripheral T Cell Lymphoma (PTCL) / Recurrent Adult Burkitt Lymphoma / Recurrent Adult Diffuse Large Cell Lymphoma / Recurrent Adult Diffuse Mixed Cell Lymphoma / Recurrent Adult Diffuse Small Cleaved Cell Lymphoma / Recurrent Adult Grade III Lymphomatoid Granulomatosis / Recurrent Adult Hodgkin's Lymphoma / Recurrent Adult Immunoblastic Large Cell Lymphoma / Recurrent Adult Lymphoblastic Lymphoma / Recurrent Adult T-Cell Leukemia/Lymphoma / Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma / Recurrent Grade 1 Follicular Lymphoma / Recurrent Grade 2 Follicular Lymphoma / Recurrent Grade 3 Follicular Lymphoma / Recurrent Mantle Cell Lymphoma / Recurrent Marginal Zone Lymphoma / Recurrent Mycosis Fungoides/Sezary Syndrome / Recurrent Small Lymphocytic Lymphoma / Refractory Multiple Myeloma / Relapsing Chronic Myelogenous Leukemia / Small Intestine Lymphoma / Splenic Marginal Zone Lymphoma / Stage III Chronic Lymphocytic Leukemia / Testicular Lymphoma / Waldenström's Macroglobulinemia (WM)1
1CompletedTreatmentNeoplastic Disease1
1CompletedTreatmentUnspecified Adult Solid Tumor, Protocol Specific1
1, 2Active Not RecruitingTreatmentAdvanced Malignant Solid Neoplasm / Peritoneal Mesothelioma Malignant Advanced / Pleural Mesothelioma Malignant Advanced / Recurrent Peritoneal Malignant Mesothelioma / Recurrent Pleural Malignant Mesothelioma / Refractory Malignant Solid Neoplasm / Unresectable Solid Neoplasm1
1, 2RecruitingTreatmentGranulosa Cell Ovarian Cancer / Malignant Lymphomas / Metastatic Colon Carcinoma / Non-Small Cell Lung Carcinoma (NSCLC) / Solid Tumors1

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 Solubility600.0 mg/mLALOGPS
logP-0.76ALOGPS
logP-0.36ChemAxon
logS1.11ALOGPS
pKa (Strongest Basic)4.32ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area35.25 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity12.33 m3·mol-1ChemAxon
Polarizability4.7 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

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

Targets

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Kind
Nucleotide
Organism
Humans
Pharmacological action
Unknown
DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.

Drug created at March 19, 2008 16:24 / Updated at June 12, 2020 16:52