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

Similar Structures

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

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	antagonist	Haloarcula marismortui (strain ATCC 43049 / DSM 3752 / JCM 8966 / VKM B-1809)
A60S ribosomal protein L3	antagonist	Humans

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

Phase	Status	Purpose	Conditions	Count
1	Completed	Not Available	Hematologic Tumors	1
1	Completed	Treatment	Malignancies, Hematologic / Tumors, Solid	1
1	Terminated	Treatment	Leukemias	1
1, 2	Active Not Recruiting	Treatment	Leukemia Acute Myeloid Leukemia (AML)	1
1, 2	Recruiting	Treatment	High Grade Myelodysplastic Syndromes	1
1, 2	Terminated	Other	Chronic Myeloid Leukemia (CML)	1
1, 2	Withdrawn	Treatment	Leukemias	1
1, 2	Withdrawn	Treatment	Myelodysplastic Syndromes	1
2	Active Not Recruiting	Treatment	Leukemias	1
2	Completed	Treatment	Acute Myelogenous Leukaemia (AML)	1
2	Completed	Treatment	Childhood Chronic Myelogenous Leukemia / Chronic Myelogenous Leukemia, BCR-ABL1 Positive / Chronic Phase Chronic Myelogenous Leukemia / Relapsing Chronic Myelogenous Leukemia	1
2	Completed	Treatment	Chronic Myelogenous Leukemia, BCR-ABL1 Positive / Chronic Phase Chronic Myelogenous Leukemia	1
2	Completed	Treatment	Chronic Myeloid Leukemia (CML)	2
2	Completed	Treatment	Leukemias	3
2	Recruiting	Treatment	FLT3-ITD Mutation / Leukemia Acute Myeloid Leukemia (AML)	2
2	Terminated	Treatment	Acute 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 Leukemia	1
2	Terminated	Treatment	Blast Phase / Chronic Myeloid Leukemia (CML) / Myeloid Leukemia, Chronic, Accelerated-Phase / Myeloid Leukemia, Chronic, Chronic-Phase	1
3	Terminated	Treatment	Leukemias	1

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
US6987103	No	2006-01-17	2023-06-28

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

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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

Details1. 50S ribosomal protein L2

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]

Details2. 60S ribosomal protein L3

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

Omacetaxine mepesuccinate

Identification

Structure for Omacetaxine mepesuccinate (DB04865)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

References