DT-Web

DB04865 - Homoharringtonine


Identification
Name Homoharringtonine
Accession Number DB04865
Type small molecule
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(TM) 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
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 545.6213
Groups approved
Monoisotopic Weight 545.262481851
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.
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.
Absorption Homoharringtonine absorption was not quantified, but maximum concentration is reached after about 30 mins.
Protein binding Plasma protein binding is equal or less than 50%.
Biotransformation 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%.
Toxicity The most severe adverse effects after homoharringtonine administration are myelosuppression, bleeding, hyperglycemia, and fetal harm.
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Acetylsalicylic acid Avoid combination with acetylsalicylic acid due to the potential enhancement of homoharringtonine associated bleeding-related adverse effects. Specifically it is suggested to avoid this combination in patients with a platelet count of less than 50,000/uL.
Ibuprofen Avoid combination with ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) due to the potential enhancement of homoharringtonine associated bleeding-related adverse effects. Specifically it is suggested to avoid this combination in patients with a platelet count of less than 50,000/uL.
Natalizumab Avoid combination due to the increased risk of infection.
Pimecrolimus Avoid combination as there is potential to increase immunosuppressant adverse effects.
Tacrolimus Avoid combination as there is potential to increase immunosuppressant adverse effects.
Tofacitinib Avoid combination with tofacitinib and other potent immunosuppressants as there is potential to increase the immunosuppressant effects. Other less potent immunosuppressants such as methotrexate, at antirheumatic doses, and other non-disease modifying antirheumatic drugs (non-DMARDs) can be combined.
Warfarin Avoid combination with warfarin and other anticoagulants due to the potential enhancement of homoharringtonine associated bleeding-related adverse effects. Specifically it is suggested to avoid this combination in patients with a platelet count of less than 50,000/uL.
Food Interactions
  • Homoharringtonine is administered subcutaneously, so food should have no effects.

Targets


50S ribosomal protein L2
Name 50S ribosomal protein L2
Gene Name Not Available
Pharmacological action yes
Actions antagonist
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
DTHybrid score Not Available
60S ribosomal protein L3
Name 60S ribosomal protein L3
Gene Name RPL3
Pharmacological action yes
Actions antagonist
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
  • 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
DTHybrid score 0.6054

Predictions


Id Partner name Gene Name Score
6329 60S ribosomal protein L19 RPL19 0.0952
6337 NHP2-like protein 1 NHP2L1 0.0952
6328 60S ribosomal protein L15 RPL15 0.0952
6332 60S ribosomal protein L26-like 1 RPL26L1 0.0952
6330 60S ribosomal protein L23a RPL23A 0.0952
6331 Probable ribosome biogenesis protein RLP24 RSL24D1 0.0952
6336 60S ribosomal protein L11 RPL11 0.0952
6326 60S ribosomal protein L13a RPL13A 0.0952
6325 60S ribosomal protein L10-like RPL10L 0.0951
6327 60S ribosomal protein L23 RPL23 0.0951
6333 60S ribosomal protein L8 RPL8 0.0951
6334 60S ribosomal protein L37 RPL37 0.0859
6831 Leucyl/phenylalanyl-tRNA--protein transferase aat 0.0401
6616 L-phenylalanine dehydrogenase pdh 0.0306
6231 Pepsin A PGA3 0.0229
6255 Carboxypeptidase A1 CPA1 0.021
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