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Identification
NameHomoharringtonine
Accession NumberDB04865
TypeSmall Molecule
GroupsApproved
Description

Homoharringtonine, AKA HHT or omacetaxine mepesuccinate, is a cephalotaxine ester and protein synthesis inhibitor with established clinical activity as a single agent in hematological malignancies. Homoharringtonine is synthesized from cephalotaxine, which is an extract from the leaves of the plant, Cephalotaxus species. In October 2005, homoharringtonine received Orphan Drug designation from the EMEA for the treatment of chronic myeloid leukemia (CML). Then in March 2006, homoharringtonine received Orphan Drug status from the FDA for the treatment of CML. In November 2006, homoharringtonine, for the treatment of CML, was granted Fast Track designation by the FDA. Most recently, in October 2012, homoharringtonine was marketed under the brand name Synribo™ and FDA approved for patients who are intolerant and/or resistant to two or more tyrosine kinase inhibitors used to treat accelerated or chronic phase CML.

Structure
Thumb
Synonyms
Cephalotaxus alkaloid
CGX-635
HHT
Myelostat
omacetaxine mepesuccinate
External Identifiers
  • NSC-141633
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Synriboinjection, powder, lyophilized, for solution3.5 mg/mLsubcutaneousCephalon, Inc.2012-11-19Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
CeflatoninChemGenex Therapeutics
Brand mixturesNot Available
SaltsNot Available
Categories
UNII6FG8041S5B
CAS number26833-87-4
WeightAverage: 545.6213
Monoisotopic: 545.262481851
Chemical FormulaC29H39NO9
InChI KeyInChIKey=HYFHYPWGAURHIV-ZEDNPHJLSA-N
InChI
InChI=1S/C29H39NO9/c1-27(2,33)8-5-10-29(34,16-23(31)36-4)26(32)39-25-22(35-3)15-28-9-6-11-30(28)12-7-18-13-20-21(38-17-37-20)14-19(18)24(25)28/h13-15,24-25,33-34H,5-12,16-17H2,1-4H3/t24-,25+,28-,29?/m0/s1
IUPAC Name
(2R,3S,6R)-4-methoxy-16,18-dioxa-10-azapentacyclo[11.7.0.0²,⁶.0⁶,¹⁰.0¹⁵,¹⁹]icosa-1(20),4,13,15(19)-tetraen-3-yl 1-methyl 3-hydroxy-3-(4-hydroxy-4-methylpentyl)butanedioate
SMILES
[H][C@]12[[email protected]](OC(=O)C(O)(CCCC(C)(C)O)CC(=O)OC)C(OC)=C[C@@]11CCCN1CCC1=CC3=C(OCO3)C=C21
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as cephalotaxus alkaloids. These are alkaloids with a structure based on the cephalotaxine skeleton, a tetracyclic 1,3-benzodioxole-containing compound which arises from the skeletal rearrangement of the hydroaromatic component of the Erythrina group.
KingdomOrganic compounds
Super ClassAlkaloids and derivatives
ClassCephalotaxus alkaloids
Sub ClassNot Available
Direct ParentCephalotaxus alkaloids
Alternative Parents
Substituents
  • Cephalotaxine
  • Cephalotaxus alkaloid skeleton
  • Benzazepine
  • Benzodioxole
  • Aralkylamine
  • Fatty acid methyl ester
  • Fatty acid ester
  • Beta-hydroxy acid
  • Azepine
  • Fatty acyl
  • Benzenoid
  • N-alkylpyrrolidine
  • Hydroxy acid
  • Dicarboxylic acid or derivatives
  • Methyl ester
  • Tertiary alcohol
  • Pyrrolidine
  • Tertiary aliphatic amine
  • Tertiary amine
  • Carboxylic acid ester
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Carboxylic acid derivative
  • Acetal
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationUsed in patients who are intolerant and/or resistant to two or more tyrosine kinase inhibitors used to treat accelerated or chronic phase CML.
PharmacodynamicsThe pharmacodynamics of homoharringtonine is not fully understood. It is known that homoharringtonine is involved with protein synthesis inhibition and this leads to its antineoplastic activity.
Mechanism of actionHomoharringtonine inhibits protein synthesis by not directly binding to Bcr-Abl. It binds to the A-site cleft in the large ribosomal subunit, which affects chain elongation and prevents protein synthesis.
Related Articles
AbsorptionHomoharringtonine absorption was not quantified, but maximum concentration is reached after about 30 mins.
Volume of distribution

Homoharringtonine has a steady state Vd of 141 ± 93.4 L.

Protein bindingPlasma protein binding is equal or less than 50%.
Metabolism

Homoharringtonine has undergoes little hepatic metabolism and is mostly metabolized to 4’-DMHHT by plasma esterase hydrolysis.

Route of eliminationThe main route of elimination for homoharringtonine is still unknown, but renal elimination is less than 15%.
Half lifeHomoharringtonine has a half life of about 6 hours after subcutaneous administration.
Clearance

Clearance for homoharringtonine was not quantified.

ToxicityThe most severe adverse effects after homoharringtonine administration are myelosuppression, bleeding, hyperglycemia, and fetal harm.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8077
Blood Brain Barrier-0.5157
Caco-2 permeable-0.5102
P-glycoprotein substrateSubstrate0.9056
P-glycoprotein inhibitor IInhibitor0.5183
P-glycoprotein inhibitor IINon-inhibitor0.8527
Renal organic cation transporterNon-inhibitor0.7406
CYP450 2C9 substrateNon-substrate0.8857
CYP450 2D6 substrateNon-substrate0.7052
CYP450 3A4 substrateSubstrate0.7613
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.923
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorInhibitor0.796
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9428
Ames testNon AMES toxic0.5243
CarcinogenicityNon-carcinogens0.909
BiodegradationNot ready biodegradable0.993
Rat acute toxicity3.1592 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9292
hERG inhibition (predictor II)Non-inhibitor0.8032
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionsubcutaneous3.5 mg/mL
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6987103 No2003-06-282023-06-28Us
USRE45128 No1999-03-162019-03-16Us
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.108 mg/mLALOGPS
logP2.09ALOGPS
logP1.88ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)12.09ChemAxon
pKa (Strongest Basic)9.42ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area123.99 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity142.07 m3·mol-1ChemAxon
Polarizability58.05 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Yaguang Liu, “Process for producing harringtonine and homoharringtonine.” U.S. Patent US4783454, issued June, 1980.

US4783454
General References
  1. Lou YJ, Qian WB, Jin J: Homoharringtonine induces apoptosis and growth arrest in human myeloma cells. Leuk Lymphoma. 2007 Jul;48(7):1400-6. [PubMed:17613769 ]
  2. Jie H, Donghua H, Xingkui X, Liang G, Wenjun W, Xiaoyan H, Zhen C: Homoharringtonine-induced apoptosis of MDS cell line MUTZ-1 cells is mediated by the endoplasmic reticulum stress pathway. Leuk Lymphoma. 2007 May;48(5):964-77. [PubMed:17487741 ]
External Links
ATC CodesL01XX40
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (170 KB)
MSDSDownload (68.5 KB)
Interactions
Drug Interactions
Drug
AcenocoumarolThe risk or severity of adverse effects can be increased when Acenocoumarol is combined with Homoharringtonine.
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Acetylsalicylic acid is combined with Homoharringtonine.
ApixabanThe risk or severity of adverse effects can be increased when Apixaban is combined with Homoharringtonine.
ArgatrobanThe risk or severity of adverse effects can be increased when Argatroban is combined with Homoharringtonine.
BivalirudinThe risk or severity of adverse effects can be increased when Bivalirudin is combined with Homoharringtonine.
CaffeineThe risk or severity of adverse effects can be increased when Caffeine is combined with Homoharringtonine.
CelecoxibThe risk or severity of adverse effects can be increased when Celecoxib is combined with Homoharringtonine.
Dabigatran etexilateThe risk or severity of adverse effects can be increased when Dabigatran etexilate is combined with Homoharringtonine.
DalteparinThe risk or severity of adverse effects can be increased when Dalteparin is combined with Homoharringtonine.
DanaparoidThe risk or severity of adverse effects can be increased when Danaparoid is combined with Homoharringtonine.
DesirudinThe risk or severity of adverse effects can be increased when Desirudin is combined with Homoharringtonine.
DiclofenacThe risk or severity of adverse effects can be increased when Diclofenac is combined with Homoharringtonine.
DiflunisalThe risk or severity of adverse effects can be increased when Diflunisal is combined with Homoharringtonine.
DihydrocodeineThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Homoharringtonine.
EdoxabanThe risk or severity of adverse effects can be increased when Edoxaban is combined with Homoharringtonine.
EnoxaparinThe risk or severity of adverse effects can be increased when Enoxaparin is combined with Homoharringtonine.
EtodolacThe risk or severity of adverse effects can be increased when Etodolac is combined with Homoharringtonine.
FenoprofenThe risk or severity of adverse effects can be increased when Fenoprofen is combined with Homoharringtonine.
FloctafenineThe risk or severity of adverse effects can be increased when Floctafenine is combined with Homoharringtonine.
FlurbiprofenThe risk or severity of adverse effects can be increased when Flurbiprofen is combined with Homoharringtonine.
Fondaparinux sodiumThe risk or severity of adverse effects can be increased when Fondaparinux sodium is combined with Homoharringtonine.
HeparinThe risk or severity of adverse effects can be increased when Heparin is combined with Homoharringtonine.
IbuprofenThe risk or severity of adverse effects can be increased when Ibuprofen is combined with Homoharringtonine.
IndomethacinThe risk or severity of adverse effects can be increased when Indomethacin is combined with Homoharringtonine.
KetoprofenThe risk or severity of adverse effects can be increased when Ketoprofen is combined with Homoharringtonine.
KetorolacThe risk or severity of adverse effects can be increased when Ketorolac is combined with Homoharringtonine.
Mefenamic acidThe risk or severity of adverse effects can be increased when Mefenamic acid is combined with Homoharringtonine.
MeloxicamThe risk or severity of adverse effects can be increased when Meloxicam is combined with Homoharringtonine.
NabumetoneThe risk or severity of adverse effects can be increased when Nabumetone is combined with Homoharringtonine.
NadroparinThe risk or severity of adverse effects can be increased when Nadroparin is combined with Homoharringtonine.
NaproxenThe risk or severity of adverse effects can be increased when Naproxen is combined with Homoharringtonine.
OxaprozinThe risk or severity of adverse effects can be increased when Oxaprozin is combined with Homoharringtonine.
PiroxicamThe risk or severity of adverse effects can be increased when Piroxicam is combined with Homoharringtonine.
RivaroxabanThe risk or severity of adverse effects can be increased when Rivaroxaban is combined with Homoharringtonine.
SulindacThe risk or severity of adverse effects can be increased when Sulindac is combined with Homoharringtonine.
Tiaprofenic acidThe risk or severity of adverse effects can be increased when Tiaprofenic acid is combined with Homoharringtonine.
TinzaparinThe risk or severity of adverse effects can be increased when Tinzaparin is combined with Homoharringtonine.
TolmetinThe risk or severity of adverse effects can be increased when Tolmetin is combined with Homoharringtonine.
WarfarinThe risk or severity of adverse effects can be increased when Warfarin is combined with Homoharringtonine.
Food Interactions
  • Homoharringtonine is administered subcutaneously, so food should have no effects.

Targets

Kind
Protein
Organism
Haloarcula marismortui (strain ATCC 43049 / DSM 3752 / JCM 8966 / VKM B-1809)
Pharmacological action
yes
Actions
antagonist
General Function:
Structural constituent of ribosome
Specific Function:
One of the primary rRNA binding proteins. Required for association of the 30S and 50S subunits to form the 70S ribosome, for tRNA binding and peptide bond formation. It has been suggested to have peptidyltransferase activity; this is somewhat controversial. Makes several contacts with the 16S rRNA in the 70S ribosome (By similarity).
Gene Name:
rpl2
Uniprot ID:
P20276
Molecular Weight:
25308.485 Da
References
  1. Gurel G, Blaha G, Moore PB, Steitz TA: U2504 determines the species specificity of the A-site cleft antibiotics: the structures of tiamulin, homoharringtonine, and bruceantin bound to the ribosome. J Mol Biol. 2009 May 29;389(1):146-56. doi: 10.1016/j.jmb.2009.04.005. Epub 2009 Apr 9. [PubMed:19362093 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Structural constituent of ribosome
Specific Function:
The L3 protein is a component of the large subunit of cytoplasmic ribosomes.
Gene Name:
RPL3
Uniprot ID:
P39023
Molecular Weight:
46108.72 Da
References
  1. Tujebajeva RM, Graifer DM, Matasova NB, Fedorova OS, Odintsov VB, Ajtkhozhina NA, Karpova GG: Selective inhibition of the polypeptide chain elongation in eukaryotic cells. Biochim Biophys Acta. 1992 Jan 6;1129(2):177-82. [PubMed:1730056 ]
  2. Tujebajeva RM, Graifer DM, Karpova GG, Ajtkhozhina NA: Alkaloid homoharringtonine inhibits polypeptide chain elongation on human ribosomes on the step of peptide bond formation. FEBS Lett. 1989 Nov 6;257(2):254-6. [PubMed:2583270 ]
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Drug created on October 19, 2007 17:15 / Updated on June 26, 2016 01:53