Repositioning Candidate Details
| Candidate ID: | R0963 |
| Source ID: | DB06263 |
| Source Type: | investigational |
| Compound Type: | small molecule |
| Compound Name: | Amrubicin |
| Synonyms: | Amrubicin |
| Molecular Formula: | C25H25NO9 |
| SMILES: | [H][C@@]1(C[C@@](N)(CC2=C1C(O)=C1C(=O)C3=CC=CC=C3C(=O)C1=C2O)C(C)=O)O[C@H]1C[C@H](O)[C@H](O)CO1 |
| Structure: |
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| DrugBank Description: | Amrubicin is a third-generation synthetic anthracycline currently in development for the treatment of small cell lung cancer. Pharmion licensed the rights to Amrubicin in November 2006. In 2002, Amrubicin was approved and launched for sale in Japan based on Phase 2 efficacy data in both SCLC and NSCLC. Since January 2005, Amrubicin has been marketed by Nippon Kayaku, a Japanese pharmaceutical firm focused on oncology, which licensed Japanese marketing rights from Dainippon Sumitomo, the original developer of Amrubicin . |
| CAS Number: | 110267-81-7 |
| Molecular Weight: | 483.473 |
| DrugBank Indication: | Investigated for use/treatment in lung cancer . |
| DrugBank Pharmacology: | The _anthracycline glycoside_ group of antibiotics, which includes amrubicin, represent a group of potent anticancer agents with potent activity against both solid tumors and hematological malignancies. They are the principal subjects of a large number of studies for the treatment of adult and childhood neoplastic diseases . Amrubicin is a 9-aminoanthracycline derivative and promotes cell growth inhibition by stabilizing protein – DNA complexes followed by double-stranded DNA breaks, which are mediated by topoisomerase-II enzyme . Anthracyclines have been observed to have a variety molecular effects (for example, DNA intercalation, inhibition of topoisomerase II, and stabilization of topoisomerase IIα cleavable complexes). Amrubicin shows decreased DNA intercalation when compared with doxorubicin. The decreased DNA interaction likely influences the intracellular distribution because amrubicin and its metabolite, _amrubicinol_. Amrubicin showed 20% distribution into the nucleus of P388 cells compared with the 80% nuclear distribution shown by doxorubicin (another anthracycline drug). The cell growth inhibitory effects of amrubicin appear to be mainly due to the inhibition of topoisomerase II . |
| DrugBank MoA: | As an anthracycline, amrubicin has antimitotic and cytotoxic activity through a variety of mechanisms of action. Amrubicin is found to form complexes with DNA via intercalation between base pairs, and it inhibits topoisomerase II enzyme activity by stabilizing the DNA-topoisomerase II complex, which prevents the re-ligation portion of the ligation-religation reaction that topoisomerase II normally catalyzes . Topoisomerase II is an enzyme located in the nucleus that regulates DNA structure through double-strand breakage and re-ligation, therefore modulating DNA replication and transcription. Inhibition of the enzyme leads to inhibition of DNA replication and halt cell growth with an arrest of the cell cycle occurring at the G2/M phase. The mechanism by which amrubicin inhibits DNA topoisomerase II is believed to be through stabilization of the cleavable DNA–topo II complex, ending in re-ligation failure and DNA strand breakage . DNA damage triggers activation of caspase-3 and -7 and cleavage of the enzyme PARP (Poly ADP ribose polymerase), leading to apoptosis and a loss of mitochondrial membrane potential. Amrubicin, like all anthracyclines, intercalates into DNA and produces reactive oxygen free radicals via interaction with NADPH, which causes cell damage . Compared with doxorubicin, another member of the anthracycline drug class, amrubicin binds DNA with a 7-fold lower affinity and therefore, higher concentrations of amrubicin are necessary to promote DNA unwinding . |
| Targets: | DNA topoisomerase 2-alpha; DNA |
| Inclusion Criteria: | Therapeutic strategy associated |
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