Repositioning Candidate Details
| Candidate ID: | R1602 |
| Source ID: | DB16627 |
| Source Type: | approved; withdrawn |
| Compound Type: | small molecule |
| Compound Name: | Melphalan flufenamide |
| Synonyms: | Melflufen; Melphalan flufenamide; MFF |
| Molecular Formula: | C24H30Cl2FN3O3 |
| SMILES: | CCOC(=O)[C@H](CC1=CC=C(F)C=C1)NC(=O)[C@@H](N)CC1=CC=C(C=C1)N(CCCl)CCCl |
| Structure: |
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| DrugBank Description: | Melphalan flufenamide, also known as melflufen or J1, is a prodrug of . Melphalan flufenamide is more readily uptaken by cells than melphalan, and is cleaved to the active metabolite by aminopeptidases. _In vitro_ models show that melphalan is 10 to hundreds of times more potent than melphalan. The increased potency makes melphalan flufenamide a treatment option for patients with relapsed or refractory multiple myeloma who have attempted at least 4 lines of therapy already. Melphalan flufenamide was granted FDA approval on 26 February 2021.. It has since been withdrawn from the market in the wake of the phase 3 OCEAN trial which showed a decrease in overall survival in comparison to standard treatment with and despite superior progression-free survival. |
| CAS Number: | 380449-51-4 |
| Molecular Weight: | 498.42 |
| DrugBank Indication: | Melphalan flufenamide is indicated in combination with to treat adults with relapsed or refractory multiple myeloma who have received ≥4 therapies and are refractory to at least one proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody. The FDA has withdrawn the drug from the market for this indication following phase 3 trial data showing decreased overall survival. |
| DrugBank Pharmacology: | Melphalan flufenamide is an alkylating agent indicated to treat relapsed or refractory multiple myeloma in Melphalan flufenamide has a long duration of action as it is given every 28 days. Patients should be counselled regarding risks of thrombocytopenia, neutropenia, anemia, infections, secondary malignancies, embryo-fetal toxicity. |
| DrugBank MoA: | Melphalan flufenamide is a more lipophilic prodrug of melphalan, which allows it to be more readily uptaken by cells. It is likely taken up into malignant cells by passive diffusion, where it is hydrolyzed by aminopeptidase N. The expression of aminopeptidases, along with other hydrolytic enzymes, is upregulated in many malignant cells, making the hydrolysis reaction to melphalan more favourable in a malignant cell. Increased concentrations of free melphalan in malignant cells leads to rapid irreversible DNA damage and apoptosis, reducing the potential for the development of resistance. Free melphalan is an nitrogen mustard derivative alkylating agent. Melphalan attaches alkyl groups to the N-7 position of guanine and N-3 position of adenine, leading to the formation of monoadducts, and DNA fragmenting when repair enzymes attempt to correct the error. It can also cause DNA cross-linking from the N-7 position of one guanine to the N-7 position of another, preventing DNA strands from separating for synthesis or transcription. Finally, melphalan can induce a number of different mutations. While melphalan induces phosphorylation of the DNA damage marker γ-H2AX in melphalan sensitive cells at 6 hours, melphalan flufenamide induces γ-H2AX at 2 hours. Melphalan flufenamide is also able to induce γ-H2AX in melphalan-resistant cells. |
| Targets: | DNA cross-linking/alkylation |
| Inclusion Criteria: | Therapeutic strategy associated |
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