Identification

Generic Name
GMX1777
DrugBank Accession Number
DB05217
Background

GMX1777 is a water-soluble prodrug of the cyanoguanidine compound GMX1778 with potential antineoplastic activity. In vivo, apoptosis inducer GMX1777 is rapidly converted into GMX1778 through hydrolytic cleavage of a carbonate ester bond. Although the exact mechanism of action has yet to be fully elucidated, GMX1778 appears to antagonize nuclear factor-kappa B (NF-kB) transcription, resulting in the induction of tumor cell apoptosis.

Type
Small Molecule
Groups
Investigational
Synonyms
Not Available

Pharmacology

Indication

Intended for the treatment of solid tumors and lymphomas.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

GMX1777 exhibits unusually potent anti-tumor activity in preclinical animal models. The novel mechanism of action of GMX1778 supports the clinical use of GMX1777 as an anti-cancer agent. Moreover, the strong dependency of cancer cells on NAD+ to support DNA repair suggests a strong rationale for the use of GMX1777 in combination with DNA damaging agents for future trials.

Mechanism of action

The cytotoxicity of GMX1777, a prodrug of GMX1778, occurs exclusively through its ability to selectively inhibit nicotinamide phosphoribosyl transferase (NAMPRT). Tumor cells have elevated NAMPRT, an enzyme involved in the biosynthesis of oxidized nicotinamide adenine dinucleotide (NAD+). These cells have a high rate of NAD+ turnover due to elevated glycolysis and high ADP-ribosylation activity required for DNA repair, genome stability and telomere maintenance. These latter characteristics make cancer cells more susceptible to NAMPRT inhibition than normal cells. Although the mechanism of action of GMX1778 was initially believed to include NF-κB inhibition, a transcriptional factor that plays a role in cancer cell survival, NF-κB inhibition occurs as a consequence of ATP loss following NAMPRT inhibition and NAD+ decline.

TargetActionsOrganism
UNicotinamide phosphoribosyltransferase
inhibitor
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

GMX1777 is rapidly converted to GMX1778 in vivo through hydrolytic cleavage of an ester carbonate bond.

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

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
D6V5QYX9MZ
CAS number
Not Available
InChI Key
Not Available
InChI
Not Available
IUPAC Name
Not Available
SMILES
Not Available

References

General References
  1. Link [Link]
PubChem Substance
347910031

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1WithdrawnTreatmentSolid Tumors and Lymphomas1
1, 2TerminatedTreatmentMetastatic Melanoma1

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
Not Available
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Nicotinate-nucleotide diphosphorylase (carboxylating) activity
Specific Function
Catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component ...
Gene Name
NAMPT
Uniprot ID
P43490
Uniprot Name
Nicotinamide phosphoribosyltransferase
Molecular Weight
55520.8 Da
References
  1. Olesen UH, Petersen JG, Garten A, Kiess W, Yoshino J, Imai S, Christensen MK, Fristrup P, Thougaard AV, Bjorkling F, Jensen PB, Nielsen SJ, Sehested M: Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase. BMC Cancer. 2010 Dec 12;10:677. doi: 10.1186/1471-2407-10-677. [Article]

Drug created at October 21, 2007 22:24 / Updated at May 04, 2022 15:51