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
Structure for Omacetaxine mepesuccinate (DB04865)
- Synonyms
- (−)-homoharringtonine
- (2'R,3S,4S,5R)-(−)-homoharringtonine
- HHT
- Homoharringtonin
- Homoharringtonine
- mepesuccinato de omacetaxina
- Omacetaxine mepesuccinate
- External IDs
- CGX-635 / NSC-141633
- Product Ingredients
Ingredient UNII CAS InChI Key Omacetaxine mepesuccinate hydrochloride 563OX5661H 457895-79-3 RRNSZQVHVKGKOS-CALFFDBBSA-N - Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Synribo Injection, powder, lyophilized, for solution 3.5 mg/1mL Subcutaneous Cephalon, Inc. 2012-11-19 Not applicable US 
- 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.
Target Actions Organism A50S ribosomal protein L2 antagonistHaloarcula marismortui (strain ATCC 43049 / DSM 3752 / JCM 8966 / VKM B-1809) A60S ribosomal protein L3 antagonistHumans - 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
Drug Interaction (R)-warfarin The risk or severity of bleeding can be increased when (R)-warfarin is combined with Omacetaxine mepesuccinate. (S)-Warfarin The risk or severity of bleeding can be increased when (S)-Warfarin is combined with Omacetaxine mepesuccinate. 4-hydroxycoumarin The risk or severity of bleeding can be increased when 4-hydroxycoumarin is combined with Omacetaxine mepesuccinate. Abciximab The risk or severity of bleeding can be increased when Abciximab is combined with Omacetaxine mepesuccinate. Aceclofenac The risk or severity of bleeding can be increased when Aceclofenac is combined with Omacetaxine mepesuccinate. Acemetacin The risk or severity of bleeding can be increased when Acemetacin is combined with Omacetaxine mepesuccinate. Acenocoumarol The risk or severity of bleeding can be increased when Acenocoumarol is combined with Omacetaxine mepesuccinate. Acetylsalicylic acid The risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Omacetaxine mepesuccinate. Acetylsalicylic acid The risk or severity of adverse effects can be increased when Acetylsalicylic acid is combined with Omacetaxine mepesuccinate. Alclofenac The 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
- 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]
- 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
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Injection, powder, lyophilized, for solution Subcutaneous 3.5 mg/1mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) USRE45128 No 2014-09-09 2019-03-16 US US6987103 No 2006-01-17 2023-06-28 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.108 mg/mL ALOGPS logP 2.09 ALOGPS logP 1.88 ChemAxon logS -3.7 ALOGPS pKa (Strongest Acidic) 12.09 ChemAxon pKa (Strongest Basic) 9.42 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 8 ChemAxon Hydrogen Donor Count 2 ChemAxon Polar Surface Area 123.99 Å2 ChemAxon Rotatable Bond Count 11 ChemAxon Refractivity 142.07 m3·mol-1 ChemAxon Polarizability 57.62 Å3 ChemAxon Number of Rings 5 ChemAxon Bioavailability 0 ChemAxon Rule of Five No ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule Yes ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption + 0.8077 Blood Brain Barrier - 0.5157 Caco-2 permeable - 0.5102 P-glycoprotein substrate Substrate 0.9056 P-glycoprotein inhibitor I Inhibitor 0.5183 P-glycoprotein inhibitor II Non-inhibitor 0.8527 Renal organic cation transporter Non-inhibitor 0.7406 CYP450 2C9 substrate Non-substrate 0.8857 CYP450 2D6 substrate Non-substrate 0.7052 CYP450 3A4 substrate Substrate 0.7613 CYP450 1A2 substrate Non-inhibitor 0.9045 CYP450 2C9 inhibitor Non-inhibitor 0.9071 CYP450 2D6 inhibitor Non-inhibitor 0.923 CYP450 2C19 inhibitor Non-inhibitor 0.9026 CYP450 3A4 inhibitor Inhibitor 0.796 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9428 Ames test Non AMES toxic 0.5243 Carcinogenicity Non-carcinogens 0.909 Biodegradation Not ready biodegradable 0.993 Rat acute toxicity 3.1592 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9292 hERG inhibition (predictor II) Non-inhibitor 0.8032
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available MS/MS Spectrum - , positive LC-MS/MS splash10-0002-0190070000-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
- 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
- Humans
- 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
- 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]
- 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 December 16, 2018 06:51