Omacetaxine mepesuccinate

Identification

Name
Omacetaxine mepesuccinate
Accession Number
DB04865
Type
Small Molecule
Groups
Approved, Investigational
Description

Omacetaxine mepesuccinate (formerly known as HHT or Homoharringtonine), is a cephalotaxine ester and protein synthesis inhibitor with established clinical activity as a single agent in hematological malignancies. Omacetaxine mepesuccinate is synthesized from cephalotaxine, which is an extract from the leaves of the plant, Cephalotaxus species. In October 2005, omacetaxine mepesuccinate received Orphan Drug designation from the EMEA for the treatment of chronic myeloid leukemia (CML). Then in March 2006, it received Orphan Drug status from the FDA for the treatment of CML. In November 2006, omacetaxine mepesuccinate, for the treatment of CML, was granted Fast Track designation by the FDA. Most recently, in October 2012, omacetaxine mepesuccinate 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
  • (−)-homoharringtonine
  • (2'R,3S,4S,5R)-(−)-homoharringtonine
  • HHT
  • Homoharringtonin
  • Homoharringtonine
  • mepesuccinato de omacetaxina
External IDs
CGX-635 / NSC-141633
Product Ingredients
IngredientUNIICASInChI Key
Omacetaxine mepesuccinate hydrochloride563OX5661H457895-79-3RRNSZQVHVKGKOS-CALFFDBBSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SynriboInjection, powder, lyophilized, for solution3.5 mg/1mLSubcutaneousCephalon, Inc.2012-11-19Not applicableUs
International/Other Brands
Ceflatonin (ChemGenex Therapeutics) / Myelostat
Categories
UNII
6FG8041S5B
CAS number
26833-87-4
Weight
Average: 545.6213
Monoisotopic: 545.262481851
Chemical Formula
C29H39NO9
InChI Key
HYFHYPWGAURHIV-JFIAXGOJSA-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-/m1/s1
IUPAC Name
(2S,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 (3R)-3-hydroxy-3-(4-hydroxy-4-methylpentyl)butanedioate
SMILES
[H][C@@]1(OC(=O)[C@@](O)(CCCC(C)(C)O)CC(=O)OC)C(OC)=C[C@]23CCCN2CCC2=CC4=C(OCO4)C=C2[C@]13[H]

Pharmacology

Indication

Used in patients who are intolerant and/or resistant to two or more tyrosine kinase inhibitors used to treat accelerated or chronic phase CML.

Associated Conditions
Pharmacodynamics

The 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 action

Homoharringtonine 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.

TargetActionsOrganism
A50S ribosomal protein L2
antagonist
Haloarcula marismortui (strain ATCC 43049 / DSM 3752 / JCM 8966 / VKM B-1809)
A60S ribosomal protein L3
antagonist
Human
Absorption

Homoharringtonine 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 binding

Plasma 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 elimination

The main route of elimination for homoharringtonine is still unknown, but renal elimination is less than 15%.

Half life

Homoharringtonine has a half life of about 6 hours after subcutaneous administration.

Clearance

Clearance for homoharringtonine was not quantified.

Toxicity

The most severe adverse effects after homoharringtonine administration are myelosuppression, bleeding, hyperglycemia, and fetal harm.

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when (R)-warfarin is combined with Omacetaxine mepesuccinate.
(S)-WarfarinThe risk or severity of bleeding can be increased when (S)-Warfarin is combined with Omacetaxine mepesuccinate.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when 4-hydroxycoumarin is combined with Omacetaxine mepesuccinate.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Omacetaxine mepesuccinate.
AceclofenacThe risk or severity of bleeding can be increased when Aceclofenac is combined with Omacetaxine mepesuccinate.
AcemetacinThe risk or severity of bleeding can be increased when Acemetacin is combined with Omacetaxine mepesuccinate.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Omacetaxine mepesuccinate.
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Acetylsalicylic acid is combined with Omacetaxine mepesuccinate.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Omacetaxine mepesuccinate.
AlclofenacThe risk or severity of bleeding can be increased when Alclofenac is combined with Omacetaxine mepesuccinate.
Food Interactions
  • Homoharringtonine is administered subcutaneously, so food should have no effects.

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
KEGG Drug
D08956
PubChem Compound
285033
PubChem Substance
175426874
ChemSpider
251215
ChEBI
71019
ChEMBL
CHEMBL46286
HET
HMT
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Omacetaxine_mepesuccinate
ATC Codes
L01XX40 — Omacetaxine mepesuccinate
PDB Entries
3g6e / 6ek0
FDA label
Download (170 KB)
MSDS
Download (68.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHematologic Tumors1
1CompletedTreatmentMalignancies, Hematologic / Tumors, Solid1
1TerminatedTreatmentLeukemias1
1, 2RecruitingTreatmentHigh Grade Myelodysplastic Syndromes1
1, 2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)1
1, 2TerminatedOtherChronic Myeloid Leukemia (CML)1
1, 2WithdrawnTreatmentLeukemias1
1, 2WithdrawnTreatmentMyelodysplastic Syndromes1
2Active Not RecruitingTreatmentLeukemias1
2CompletedTreatmentAcute Myelogenous Leukaemia (AML)1
2CompletedTreatmentChildhood Chronic Myelogenous Leukemia / Chronic Myelogenous Leukemia, BCR-ABL1 Positive / Chronic Phase Chronic Myelogenous Leukemia / Relapsing Chronic Myelogenous Leukemia1
2CompletedTreatmentChronic Myelogenous Leukemia, BCR-ABL1 Positive / Chronic Phase Chronic Myelogenous Leukemia1
2CompletedTreatmentChronic Myeloid Leukemia (CML)2
2CompletedTreatmentLeukemias3
2RecruitingTreatmentFLT3-ITD Mutation / Leukemia Acute Myeloid Leukemia (AML)1
2TerminatedTreatmentAcute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome / Adult Acute Megakaryoblastic Leukemia (M7) / Adult Acute Minimally Differentiated Myeloid Leukemia (M0) / Adult Acute Monoblastic Leukemia (M5a) / Adult Acute Monocytic Leukemia (M5b) / Adult Acute Myeloblastic Leukemia With Maturation (M2) / Adult Acute Myeloblastic Leukemia Without Maturation (M1) / Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities / Adult Acute Myeloid Leukemia With Del(5q) / Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) / Adult Acute Myeloid Leukemia With T(16;16)(p13;q22) / Adult Acute Myeloid Leukemia With T(8;21)(q22;q22) / Adult Acute Myelomonocytic Leukemia (M4) / Adult Erythroleukemia (M6a) / Adult Pure Erythroid Leukemia (M6b) / Secondary Acute Myeloid Leukemia (Secondary AML, sAML) / Untreated Adult Acute Myeloid Leukemia1
2TerminatedTreatmentBlast Phase / Chronic Myeloid Leukemia (CML) / Myeloid Leukemia, Chronic, Accelerated-Phase / Myeloid Leukemia, Chronic, Chronic-Phase1
3TerminatedTreatmentLeukemias1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionSubcutaneous3.5 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
USRE45128No1999-03-162019-03-16Us
US6987103No2003-06-282023-06-28Us

Properties

State
Solid
Experimental Properties
Not 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
Polarizability57.62 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0002-0190070000-a017ab46c2f836fe8c26

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Alkaloids and derivatives
Class
Cephalotaxus alkaloids
Sub Class
Not Available
Direct Parent
Cephalotaxus alkaloids
Alternative Parents
Benzazepines / Benzodioxoles / Aralkylamines / Azepines / Fatty acid methyl esters / Benzenoids / Dicarboxylic acids and derivatives / N-alkylpyrrolidines / Tertiary alcohols / Methyl esters
show 9 more
Substituents
Cephalotaxine / Cephalotaxus alkaloid skeleton / Benzazepine / Benzodioxole / Fatty acid methyl ester / Azepine / Fatty acid ester / Aralkylamine / N-alkylpyrrolidine / Benzenoid
show 25 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
tertiary alcohol, organic heteropentacyclic compound, alkaloid ester, enol ether (CHEBI:71019)

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 p...
Gene Name
rpl2
Uniprot ID
P20276
Uniprot Name
50S ribosomal protein L2
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
Uniprot Name
60S ribosomal protein L3
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]

Drug created on October 19, 2007 17:15 / Updated on November 02, 2018 08:59