Irofulven

Identification

Name
Irofulven
Accession Number
DB05786  (DB11733)
Type
Small Molecule
Groups
Investigational
Description

A novel anti-cancer compound synthesized by scientists at the University of California, San Diego more than a decade ago from toxins of the poisonous jack-o-lantern mushroom, has been granted “fast track” status by the U.S. Food and Drug Administration (FDA) after demonstrating promise against one of the most deadly cancers.

MGI-114 (Irofulven) is currently being developed by MGI PHARMA, Inc., an emerging oncology-focused pharmaceutical company based in Minneapolis. Phase III clinical trials involving the drug have been underway since early 2001 at sites in the U.S. and Europe.

Structure
Thumb
Synonyms
  • 6-hydroxymethylacylfulvene
  • HMAF
External IDs
MGI 114 / MGI-114 / NSC-683863
Product Ingredients
Not Available
Approved Prescription Products
Not Available
Approved Generic Prescription Products
Not Available
Approved Over the Counter Products
Not Available
Unapproved/Other Products
Not Available
International/Other Brands
Irofulven
Brand mixtures
Not Available
Categories
UNII
6B799IH05A
CAS number
158440-71-2
Weight
Average: 246.3016
Monoisotopic: 246.125594442
Chemical Formula
C15H18O3
InChI Key
NICJCIQSJJKZAH-AWEZNQCLSA-N
InChI
InChI=1S/C15H18O3/c1-8-6-10-12(11(8)7-16)9(2)15(4-5-15)14(3,18)13(10)17/h6,16,18H,4-5,7H2,1-3H3/t14-/m0/s1
IUPAC Name
(6'R)-6'-hydroxy-3'-(hydroxymethyl)-2',4',6'-trimethyl-6',7'-dihydrospiro[cyclopropane-1,5'-indene]-7'-one
SMILES
CC1=C(CO)C2=C(C)C3(CC3)[[email protected]@](C)(O)C(=O)C2=C1

Pharmacology

Indication

Investigated for use/treatment in brain cancer, breast cancer, endometrial cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, pediatric indications, prostate cancer, and sarcoma.

Structured Indications
Not Available
Pharmacodynamics
Not Available
Mechanism of action

MGI-114(Irofulven) has unique mechanism of action as an anti-tumor agent is due to its ability to be rapidly absorbed by tumor cells. Once inside the cells, the compound binds to DNA and protein targets. This binding interferes with DNA replication and cell division of tumor cells, leading to tumor-specific apoptotic cell death, or “cell suicide.” During this process, tumor cells tend to automatically shut themselves down when they sense their function is compromised.

TargetActionsOrganism
UFar upstream element-binding protein 1Not AvailableHuman
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
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of MGI-114.Approved
BevacizumabBevacizumab may increase the cardiotoxic activities of MGI-114.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with MGI-114.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of MGI-114.Approved, Investigational
DeslanosideDeslanoside may decrease the cardiotoxic activities of MGI-114.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of MGI-114.Approved
DigoxinDigoxin may decrease the cardiotoxic activities of MGI-114.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with MGI-114.Approved, Investigational
OleandrinAnvirzel may decrease the cardiotoxic activities of MGI-114.Experimental
OuabainOuabain may decrease the cardiotoxic activities of MGI-114.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with MGI-114.Approved, Vet Approved
TrastuzumabTrastuzumab may increase the cardiotoxic activities of MGI-114.Approved, Investigational
Food Interactions
Not Available

References

Synthesis Reference
Not Available
General References
  1. Kelner MJ, McMorris TC, Estes L, Samson KM, Trani NA, MacDonald JR: Anti-leukemic action of the novel agent MGI 114 (HMAF) and synergistic action with topotecan. Leukemia. 2000 Jan;14(1):136-41. [PubMed:10637489 ]
  2. Leggas M, Stewart CF, Woo MH, Fouladi M, Cheshire PJ, Peterson JK, Friedman HS, Billups C, Houghton PJ: Relation between Irofulven (MGI-114) systemic exposure and tumor response in human solid tumor xenografts. Clin Cancer Res. 2002 Sep;8(9):3000-7. [PubMed:12231547 ]
External Links
PubChem Compound
148189
PubChem Substance
175427030
ChemSpider
130640
BindingDB
50410835
ChEBI
135002
ChEMBL
CHEMBL118218
Wikipedia
Irofulven
ATC Codes
Not Available
AHFS Codes
Not Available
PDB Entries
Not Available
FDA label
Not Available
MSDS
Not Available

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentLeukemias / Myelodysplastic Syndromes1
1CompletedTreatmentUnspecified Childhood Solid Tumor, Protocol Specific1
1, 2Active Not RecruitingTreatmentLiver Cancer1
1, 2CompletedTreatmentBrain and Central Nervous System Tumors1
2CompletedTreatmentCancer, Breast1
2CompletedTreatmentCancer, Ovarian / Fallopian Tube Cancer / Primary Peritoneal Cavity Cancer1
2CompletedTreatmentCervical Cancers1
2CompletedTreatmentColorectal Cancers1
2CompletedTreatmentEndometrial Cancers1
2CompletedTreatmentLung Cancers1
2CompletedTreatmentMalignant Neoplasm of Pancreas1
2CompletedTreatmentMalignant Neoplasm of Stomach1
2CompletedTreatmentMelanoma (Skin)1
2CompletedTreatmentPrimary Peritoneal Cavity Cancer / Recurrent Ovarian Epithelial Cancer1
2CompletedTreatmentProstate Cancer1
2CompletedTreatmentRenal Cancers1
2CompletedTreatmentThyroid Cancers1
2WithdrawnTreatmentColorectal Cancers1
3CompletedTreatmentMalignant Neoplasm of Pancreas1

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 Solubility0.52 mg/mLALOGPS
logP1.19ALOGPS
logP0.67ChemAxon
logS-2.7ALOGPS
pKa (Strongest Acidic)12.77ChemAxon
pKa (Strongest Basic)-1.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area57.53 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity70.91 m3·mol-1ChemAxon
Polarizability27.33 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.8897
Caco-2 permeable+0.6632
P-glycoprotein substrateSubstrate0.6081
P-glycoprotein inhibitor INon-inhibitor0.8341
P-glycoprotein inhibitor IINon-inhibitor0.7901
Renal organic cation transporterNon-inhibitor0.7904
CYP450 2C9 substrateNon-substrate0.8237
CYP450 2D6 substrateNon-substrate0.8562
CYP450 3A4 substrateSubstrate0.6744
CYP450 1A2 substrateNon-inhibitor0.5914
CYP450 2C9 inhibitorNon-inhibitor0.7017
CYP450 2D6 inhibitorNon-inhibitor0.8684
CYP450 2C19 inhibitorNon-inhibitor0.7898
CYP450 3A4 inhibitorNon-inhibitor0.8441
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5946
Ames testAMES toxic0.8571
CarcinogenicityNon-carcinogens0.9225
BiodegradationNot ready biodegradable0.9325
Rat acute toxicity2.0258 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9857
hERG inhibition (predictor II)Non-inhibitor0.8462
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 GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted LC-MS/MS Spectrum - 10V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 20V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 40V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 10V, NegativePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 20V, NegativePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 40V, NegativePredicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of chemical entities known as cyclohexenones. These are compounds containing a cylohexenone moiety, which is a six-membered aliphatic ring that carries a ketone and has one endocyclic double bond.
Kingdom
Chemical entities
Super Class
Organic compounds
Class
Organic oxygen compounds
Sub Class
Organooxygen compounds
Direct Parent
Cyclohexenones
Alternative Parents
Acyloins / Tertiary alcohols / Primary alcohols / Organic oxides / Hydrocarbon derivatives
Substituents
Cyclohexenone / Acyloin / Tertiary alcohol / Organic oxide / Hydrocarbon derivative / Primary alcohol / Alcohol / Aliphatic homopolycyclic compound
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Transcriptional activator activity, rna polymerase ii distal enhancer sequence-specific binding
Specific Function
Regulates MYC expression by binding to a single-stranded far-upstream element (FUSE) upstream of the MYC promoter. May act both as activator and repressor of transcription.
Gene Name
FUBP1
Uniprot ID
Q96AE4
Uniprot Name
Far upstream element-binding protein 1
Molecular Weight
67560.205 Da
Drug created on November 18, 2007 11:27 / Updated on September 01, 2017 11:25