Halofuginone

Identification

Name
Halofuginone
Accession Number
DB04866
Type
Small Molecule
Groups
Investigational, Vet Approved
Description

Halofuginone is a low molecular weight quinazolinone alkaloid, and a potent inhibitor of collagen alpha1(I) and matrix metalloproteinase 2 (MMP-2) gene expression. Halofuginone also effectively suppresses tumor progression and metastasis in mice. Collgard Biopharmaceuticals is developing halofuginone for the treatment of scleroderma and received orphan drug designation from the U.S. Food and Drug Administration in March, 2000.

Structure
Thumb
Synonyms
  • (+/-)-trans-7-bromo-6-chloro-3-(3-(3-hydroxy-2-piperidyl)-acetonyl)-4(3H)-quinazolinone
External IDs
HT-100
Product Ingredients
IngredientUNIICASInChI Key
Halofuginone hydrobromidePTC2969MV164924-67-0SJUWEPZBTXEUMU-LIOBNPLQSA-N
Halofuginone lactate6ZO4HT041C82186-71-8GATQERNJKZPJNX-LIOBNPLQSA-N
International/Other Brands
Halocur / Stenorol / Tempostatin
Categories
UNII
L31MM1385E
CAS number
55837-20-2
Weight
Average: 414.681
Monoisotopic: 413.014181779
Chemical Formula
C16H17BrClN3O3
InChI Key
LVASCWIMLIKXLA-CABCVRRESA-N
InChI
InChI=1S/C16H17BrClN3O3/c17-11-6-13-10(5-12(11)18)16(24)21(8-20-13)7-9(22)4-14-15(23)2-1-3-19-14/h5-6,8,14-15,19,23H,1-4,7H2/t14-,15+/m1/s1
IUPAC Name
7-bromo-6-chloro-3-{3-[(2R,3S)-3-hydroxypiperidin-2-yl]-2-oxopropyl}-3,4-dihydroquinazolin-4-one
SMILES
[H][[email protected]]1(O)CCCN[[email protected]]1([H])CC(=O)CN1C=NC2=C(C=C(Cl)C(Br)=C2)C1=O

Pharmacology

Indication

For the treatment of scleroderma, cancer, and restenosis.

Structured Indications
Not Available
Pharmacodynamics

Halofuginone, a fully synthetic small molecule, is a potent and selective regulator of stromal cell activation, cell migration and Collagen type I synthesis, a process that has been identified as a 'master switch' in the body's tissue repair process.

Mechanism of action

Halofuginone is a potent inhibitor of collagen a1(I) and matrix metalloproteinase 2 (MMP-2) gene expression. Halofuginone also suppresses extracellular matrix deposition and cell proliferation. The profound antitumoral effect of halofuginone is attributed to its combined inhibition of the tumor stromal support, vascularization, invasiveness, and cell proliferation.

TargetActionsOrganism
UCollagen alpha-1(I) chainNot AvailableHuman
U72 kDa type IV collagenaseNot AvailableHuman
Absorption

Readily bioavailable and rapidly absorbed following oral administration.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

23.8 to 72.1 hours

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
  • Protozoa
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Halofuginone.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Halofuginone.Experimental
BevacizumabBevacizumab may increase the cardiotoxic activities of Halofuginone.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Halofuginone.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Halofuginone.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Halofuginone.Experimental
DeslanosideDeslanoside may decrease the cardiotoxic activities of Halofuginone.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Halofuginone.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Halofuginone.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Halofuginone.Approved, Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Halofuginone.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Halofuginone.Experimental
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Halofuginone.Experimental
OleandrinOleandrin may decrease the cardiotoxic activities of Halofuginone.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Halofuginone.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Halofuginone.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Halofuginone.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Halofuginone.Experimental
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Halofuginone.Approved, Investigational
Food Interactions
Not Available

References

General References
  1. Elkin M, Miao HQ, Nagler A, Aingorn E, Reich R, Hemo I, Dou HL, Pines M, Vlodavsky I: Halofuginone: a potent inhibitor of critical steps in angiogenesis progression. FASEB J. 2000 Dec;14(15):2477-85. [PubMed:11099465]
  2. Sundrud MS, Koralov SB, Feuerer M, Calado DP, Kozhaya AE, Rhule-Smith A, Lefebvre RE, Unutmaz D, Mazitschek R, Waldner H, Whitman M, Keller T, Rao A: Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science. 2009 Jun 5;324(5932):1334-8. doi: 10.1126/science.1172638. [PubMed:19498172]
  3. Keller TL, Zocco D, Sundrud MS, Hendrick M, Edenius M, Yum J, Kim YJ, Lee HK, Cortese JF, Wirth DF, Dignam JD, Rao A, Yeo CY, Mazitschek R, Whitman M: Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat Chem Biol. 2012 Feb 12;8(3):311-7. doi: 10.1038/nchembio.790. [PubMed:22327401]
External Links
KEGG Drug
D04413
PubChem Compound
456390
PubChem Substance
175426875
ChemSpider
401856
ChEMBL
CHEMBL1199540
HET
HFG
Wikipedia
Halofuginone
PDB Entries
4hvc / 4k88 / 4olf / 4q15 / 4ydq / 5f9z

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentUnspecified Adult Solid Tumor, Protocol Specific1
1, 2TerminatedTreatmentDuchenne's Muscular Dystrophy (DMD)1
2CompletedTreatmentKaposi's Sarcoma AIDS Related / Recurrent Kaposi's Sarcoma1
2TerminatedTreatmentDuchenne's Muscular Dystrophy (DMD)2

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 Solubility0.114 mg/mLALOGPS
logP1.38ALOGPS
logP1.71ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)14.48ChemAxon
pKa (Strongest Basic)9.28ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area82 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity95.87 m3·mol-1ChemAxon
Polarizability37.17 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9465
Blood Brain Barrier-0.938
Caco-2 permeable-0.7265
P-glycoprotein substrateSubstrate0.6967
P-glycoprotein inhibitor INon-inhibitor0.6713
P-glycoprotein inhibitor IIInhibitor0.584
Renal organic cation transporterNon-inhibitor0.6585
CYP450 2C9 substrateNon-substrate0.78
CYP450 2D6 substrateNon-substrate0.744
CYP450 3A4 substrateSubstrate0.5212
CYP450 1A2 substrateInhibitor0.5391
CYP450 2C9 inhibitorInhibitor0.5325
CYP450 2D6 inhibitorNon-inhibitor0.7765
CYP450 2C19 inhibitorInhibitor0.5863
CYP450 3A4 inhibitorInhibitor0.5591
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7138
Ames testNon AMES toxic0.7227
CarcinogenicityNon-carcinogens0.8721
BiodegradationNot ready biodegradable0.9869
Rat acute toxicity2.3967 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.771
hERG inhibition (predictor II)Inhibitor0.811
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 quinazolines. These are compounds containing a quinazoline moiety, which is made up of two fused six-member aromatic rings, a benzene ring and a pyrimidine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Quinazolines
Alternative Parents
Pyrimidones / Piperidines / Aryl bromides / Aryl chlorides / Benzenoids / Beta-amino ketones / Heteroaromatic compounds / Secondary alcohols / 1,2-aminoalcohols / Lactams
show 7 more
Substituents
Quinazoline / Pyrimidone / Aryl bromide / Aryl chloride / Aryl halide / Beta-aminoketone / Benzenoid / Pyrimidine / Piperidine / Heteroaromatic compound
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Platelet-derived growth factor binding
Specific Function
Type I collagen is a member of group I collagen (fibrillar forming collagen).
Gene Name
COL1A1
Uniprot ID
P02452
Uniprot Name
Collagen alpha-1(I) chain
Molecular Weight
138941.105 Da
References
  1. Elkin M, Miao HQ, Nagler A, Aingorn E, Reich R, Hemo I, Dou HL, Pines M, Vlodavsky I: Halofuginone: a potent inhibitor of critical steps in angiogenesis progression. FASEB J. 2000 Dec;14(15):2477-85. [PubMed:11099465]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Zinc ion binding
Specific Function
Ubiquitinous metalloproteinase that is involved in diverse functions such as remodeling of the vasculature, angiogenesis, tissue repair, tumor invasion, inflammation, and atherosclerotic plaque rup...
Gene Name
MMP2
Uniprot ID
P08253
Uniprot Name
72 kDa type IV collagenase
Molecular Weight
73881.695 Da
References
  1. Elkin M, Miao HQ, Nagler A, Aingorn E, Reich R, Hemo I, Dou HL, Pines M, Vlodavsky I: Halofuginone: a potent inhibitor of critical steps in angiogenesis progression. FASEB J. 2000 Dec;14(15):2477-85. [PubMed:11099465]

Drug created on October 19, 2007 17:34 / Updated on November 09, 2017 03:48