Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C24H30Cl2FN3O3.ClH |
| Molecular Weight | 534.879 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 2 / 2 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
Cl.CCOC(=O)[C@H](CC1=CC=C(F)C=C1)NC(=O)[C@@H](N)CC2=CC=C(C=C2)N(CCCl)CCCl
InChI
InChIKey=ZCMWSKHHXLCVHI-VROPFNGYSA-N
InChI=1S/C24H30Cl2FN3O3.ClH/c1-2-33-24(32)22(16-18-3-7-19(27)8-4-18)29-23(31)21(28)15-17-5-9-20(10-6-17)30(13-11-25)14-12-26;/h3-10,21-22H,2,11-16,28H2,1H3,(H,29,31);1H/t21-,22-;/m0./s1
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/23584492 | https://www.ncbi.nlm.nih.gov/pubmed/29029544 | https://www.oncopeptides.se/en/about-ygalo/http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdfCurator's Comment: description was created based on several sources, including,http://www.nhs.uk/ipgmedia/National/Macmillan%20Cancer%20Support/assets/MelphalanMCS5pages.pdf
http://www.bloodjournal.org/content/bloodjournal/100/1/224.full.pdf
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23584492 | https://www.ncbi.nlm.nih.gov/pubmed/29029544 | https://www.oncopeptides.se/en/about-ygalo/http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdf
Curator's Comment: description was created based on several sources, including,http://www.nhs.uk/ipgmedia/National/Macmillan%20Cancer%20Support/assets/MelphalanMCS5pages.pdf
http://www.bloodjournal.org/content/bloodjournal/100/1/224.full.pdf
Melphalan, also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin, is a phenylalanine derivative of nitrogen mustard. Melphalan is a bifunctional alkylating agent which produces a number of DNA adducts with the DNA interstrand crosslink (ICL) considered to be the critical cytotoxic lesion. Melphalan is used to treat different cancers including myeloma, melanoma and ovarian cancer.
Originator
Sources: https://adisinsight.springer.com/drugs/800033866http://pmj.bmj.com/content/34/398/622.full.pdf
Curator's Comment: This substance was synthesized simultaneously both at the Chester Beatty Research Institute and in the Soviet Union.
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL2311221 |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Palliative | ALKERAN Approved UseALKERAN Tablets are indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Launch Date1964 |
|||
| Palliative | ALKERAN Approved UseALKERAN Tablets are indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Launch Date1964 |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
212 ng/mL |
0.25 mg/kg single, oral dose: 0.25 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
MELPHALAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
12.84 mg × h/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26879446 |
200 mg/m² single, intravenous dose: 200 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
MELPHALAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
498 ng × h/mL |
0.25 mg/kg single, oral dose: 0.25 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
MELPHALAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
1 h |
0.25 mg/kg single, oral dose: 0.25 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
MELPHALAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Funbound
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
70% |
MELPHALAN plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Doses
| Dose | Population | Adverse events |
|---|---|---|
40 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose Dose: 40 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 40 mg/m2, 1 times / 3 weeks Sources: Page: p.60 |
unhealthy, 18–74 n = 7 Health Status: unhealthy Condition: Advanced cancer Age Group: 18–74 Sex: M+F Population Size: 7 Sources: Page: p.60 |
DLT: Thrombocytopenia, Neutropenia... Dose limiting toxicities: Thrombocytopenia (grade 4, 57%) Sources: Page: p.60Neutropenia (grade 4, 57%) |
30 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 30 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 30 mg/m2, 1 times / 3 weeks Sources: Page: p.60 |
unhealthy, 18–74 n = 9 Health Status: unhealthy Condition: Advanced cancer Age Group: 18–74 Sex: M+F Population Size: 9 Sources: Page: p.60 |
DLT: Thrombocytopenia, Neutropenia... Dose limiting toxicities: Thrombocytopenia (grade 4, 44%) Sources: Page: p.60Neutropenia (grade 4, 44%) |
200 mg/m2 1 times / 70 days multiple, intravenous MTD Dose: 200 mg/m2, 1 times / 70 days Route: intravenous Route: multiple Dose: 200 mg/m2, 1 times / 70 days Sources: Page: p.248, 250 |
unhealthy, 33–65 n = 55 Health Status: unhealthy Condition: Multiple myeloma Age Group: 33–65 Sex: M+F Population Size: 55 Sources: Page: p.248, 250 |
Disc. AE: Toxic reaction (NOS), Bacterial infection... AEs leading to discontinuation/dose reduction: Toxic reaction (NOS) (grade 4, 1.8%) Sources: Page: p.248, 250Bacterial infection (grade 5, 3.6%) Systemic herpes zoster infection (grade 5, 1.8%) |
100 mg/m2 1 times / day multiple, intravenous Recommended Dose: 100 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: Page: p.1 |
Disc. AE: Bone marrow depression, Hypersensitivity reaction... AEs leading to discontinuation/dose reduction: Bone marrow depression (severe) Sources: Page: p.1Hypersensitivity reaction (2%) Anaphylaxis Gastrointestinal toxicity Nausea Vomiting Diarrhea Mucositis oral Fetal damage Infertility |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Neutropenia | grade 4, 57% DLT |
40 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose Dose: 40 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 40 mg/m2, 1 times / 3 weeks Sources: Page: p.60 |
unhealthy, 18–74 n = 7 Health Status: unhealthy Condition: Advanced cancer Age Group: 18–74 Sex: M+F Population Size: 7 Sources: Page: p.60 |
| Thrombocytopenia | grade 4, 57% DLT |
40 mg/m2 1 times / 3 weeks multiple, intravenous Highest studied dose Dose: 40 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 40 mg/m2, 1 times / 3 weeks Sources: Page: p.60 |
unhealthy, 18–74 n = 7 Health Status: unhealthy Condition: Advanced cancer Age Group: 18–74 Sex: M+F Population Size: 7 Sources: Page: p.60 |
| Neutropenia | grade 4, 44% DLT |
30 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 30 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 30 mg/m2, 1 times / 3 weeks Sources: Page: p.60 |
unhealthy, 18–74 n = 9 Health Status: unhealthy Condition: Advanced cancer Age Group: 18–74 Sex: M+F Population Size: 9 Sources: Page: p.60 |
| Thrombocytopenia | grade 4, 44% DLT |
30 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 30 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 30 mg/m2, 1 times / 3 weeks Sources: Page: p.60 |
unhealthy, 18–74 n = 9 Health Status: unhealthy Condition: Advanced cancer Age Group: 18–74 Sex: M+F Population Size: 9 Sources: Page: p.60 |
| Toxic reaction (NOS) | grade 4, 1.8% Disc. AE |
200 mg/m2 1 times / 70 days multiple, intravenous MTD Dose: 200 mg/m2, 1 times / 70 days Route: intravenous Route: multiple Dose: 200 mg/m2, 1 times / 70 days Sources: Page: p.248, 250 |
unhealthy, 33–65 n = 55 Health Status: unhealthy Condition: Multiple myeloma Age Group: 33–65 Sex: M+F Population Size: 55 Sources: Page: p.248, 250 |
| Systemic herpes zoster infection | grade 5, 1.8% Disc. AE |
200 mg/m2 1 times / 70 days multiple, intravenous MTD Dose: 200 mg/m2, 1 times / 70 days Route: intravenous Route: multiple Dose: 200 mg/m2, 1 times / 70 days Sources: Page: p.248, 250 |
unhealthy, 33–65 n = 55 Health Status: unhealthy Condition: Multiple myeloma Age Group: 33–65 Sex: M+F Population Size: 55 Sources: Page: p.248, 250 |
| Bacterial infection | grade 5, 3.6% Disc. AE |
200 mg/m2 1 times / 70 days multiple, intravenous MTD Dose: 200 mg/m2, 1 times / 70 days Route: intravenous Route: multiple Dose: 200 mg/m2, 1 times / 70 days Sources: Page: p.248, 250 |
unhealthy, 33–65 n = 55 Health Status: unhealthy Condition: Multiple myeloma Age Group: 33–65 Sex: M+F Population Size: 55 Sources: Page: p.248, 250 |
| Hypersensitivity reaction | 2% Disc. AE |
100 mg/m2 1 times / day multiple, intravenous Recommended Dose: 100 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: Page: p.1 |
| Anaphylaxis | Disc. AE | 100 mg/m2 1 times / day multiple, intravenous Recommended Dose: 100 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: Page: p.1 |
| Diarrhea | Disc. AE | 100 mg/m2 1 times / day multiple, intravenous Recommended Dose: 100 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: Page: p.1 |
| Fetal damage | Disc. AE | 100 mg/m2 1 times / day multiple, intravenous Recommended Dose: 100 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: Page: p.1 |
| Gastrointestinal toxicity | Disc. AE | 100 mg/m2 1 times / day multiple, intravenous Recommended Dose: 100 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: Page: p.1 |
| Infertility | Disc. AE | 100 mg/m2 1 times / day multiple, intravenous Recommended Dose: 100 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: Page: p.1 |
| Mucositis oral | Disc. AE | 100 mg/m2 1 times / day multiple, intravenous Recommended Dose: 100 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: Page: p.1 |
| Nausea | Disc. AE | 100 mg/m2 1 times / day multiple, intravenous Recommended Dose: 100 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: Page: p.1 |
| Vomiting | Disc. AE | 100 mg/m2 1 times / day multiple, intravenous Recommended Dose: 100 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: Page: p.1 |
| Bone marrow depression | severe Disc. AE |
100 mg/m2 1 times / day multiple, intravenous Recommended Dose: 100 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / day Sources: Page: p.1 |
unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: Page: p.1 |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Prolonged apnea after succinylcholine in a case treated with cytostatics for cancer. | 1972 Sep-Oct |
|
| [Diagnosis and treatment of plasma cell leukemia]. | 1973 Apr 27 |
|
| Carcinoma of the breast. Occurence after treatment with melphalan for multiple myeloma. | 1976 Oct 4 |
|
| [Refractory anemia with partial myeloblastosis in multiple myeloma treated with melphalan]. | 1977 Apr 9-16 |
|
| Cytomegalovirus pneumonia after treatment with melphalan and prednisone. Report of a case. | 1978 |
|
| Lymphocyte transformation studies in drug hypersensitivity. | 1979 May 5 |
|
| Drug testing using a soft agar stem cell assay on patient and xenograft tumor material. | 1984 Sep |
|
| Melphalan-resistant multiple myeloma: results of treatment according to the M-2 protocol. | 1985 |
|
| Syndrome of inappropriate antidiuretic hormone secretion. A complication of high-dose intravenous melphalan. | 1985 Jan 1 |
|
| Altered pharmacokinetics in the mechanism of chemosensitization: effects of nitroimidazoles and other chemical modifiers on the pharmacokinetics, antitumour activity and acute toxicity of selected nitrogen mustards. | 1986 |
|
| L-phenylalanine mustard-dianhydrogalactitol and hyponatremia. | 1986 |
|
| Interferon alfa-2b/melphalan/prednisone in previously untreated patients with multiple myeloma: a phase I-II trial. | 1987 |
|
| Successful treatment of peripheral neuropathy with chemotherapy in osteosclerotic myeloma. | 1987 May |
|
| [A case report of acute renal failure induced by melphalan in a patient with ovarian cancer]. | 1988 Nov |
|
| Prednisone mood disorder with associated catatonia. | 1989 Jan-Mar |
|
| Cytogenetic abnormalities in acute leukemia complicating melphalan-treated multiple myeloma. | 1990 Aug 1 |
|
| [Enhancing factors in the cardiotoxicity of anthracyclines]. | 1990 Jan |
|
| [Hepatic veno-occlusive disease in a patient undergoing bone marrow autotransplant after busulfan and melphalan conditioning]. | 1990 Jan 27 |
|
| Interaction of melphalan and dexamethasone in a human myeloma cell line. | 1991 Dec |
|
| Multiple myeloma with coexistent myelofibrosis: improvement of myelofibrosis following recovery from multiple myeloma after treatment with melphalan and prednisolone. | 1991 Sep-Oct |
|
| SWOG 8825: melphalan GM-CSF: a phase I study. | 1992 Jan |
|
| [White blood cell lysis syndrome after autologous peripheral blood stem cell transplantation in the treatment of renal AL amyloidosis. Case report]. | 2006 Jun |
|
| The effect of intracellular ascorbate on the susceptibility of HL60 and Jurkat cells to chemotherapy agents. | 2006 Oct |
|
| Fatal leukoencephalopathy after reduced-intensity allogeneic stem cell transplantation. | 2007 Feb |
|
| Disseminated necrotizing leukoencephalopathy following low-dose oral methotrexate. | 2007 Mar |
|
| Cross-linking of the DNA repair protein Omicron6-alkylguanine DNA alkyltransferase to DNA in the presence of antitumor nitrogen mustards. | 2008 Apr |
|
| Pharmacologic profiling of human and rat cytochrome P450 1A1 and 1A2 induction and competition. | 2008 Dec |
|
| Heterogeneity of human glioblastoma: glutathione-S-transferase and methylguanine-methyltransferase. | 2008 Jul |
|
| Long-term risk of myelodysplasia in melphalan-treated patients with immunoglobulin light-chain amyloidosis. | 2008 Sep |
|
| Cardiac toxicity of high-dose cyclophosphamide and melphalan in patients with multiple myeloma treated with tandem autologous hematopoietic stem cell transplantation. | 2008 Sep |
|
| Cutaneous involvement in multiple myeloma and bortezomib. | 2009 Nov |
|
| Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. | 2010 Dec 2 |
|
| Uptake of 3-[125I]iodo-alpha-methyl-L-tyrosine into colon cancer DLD-1 cells: characterization and inhibitory effect of natural amino acids and amino acid-like drugs. | 2010 Feb |
|
| Thalidomide-induced phrenic nerve paralysis. | 2010 Feb |
|
| Glutathione S-transferase M1 inhibits dexamethasone-induced apoptosis in association with the suppression of Bim through dual mechanisms in a lymphoblastic leukemia cell line. | 2010 Mar |
|
| Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. | 2010 Nov |
|
| Inhalation of alkylating mustard causes long-term T cell-dependent inflammation in airways and growth of connective tissue. | 2011 Feb 27 |
|
| Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study. | 2011 Jan |
|
| Bone marrow osteoblast damage by chemotherapeutic agents. | 2012 |
|
| Efficient monitoring of in vivo pig-a gene mutation and chromosomal damage: summary of 7 published studies and results from 11 new reference compounds. | 2012 Dec |
|
| Increased expression of VDAC1 sensitizes carcinoma cells to apoptosis induced by DNA cross-linking agents. | 2012 May 1 |
|
| Corticosteroid treatment inhibits airway hyperresponsiveness and lung injury in a murine model of chemical-induced airway inflammation. | 2012 Nov 15 |
|
| In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells. | 2013 Jun 1 |
|
| The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo. | 2013 Oct 1 |
|
| FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-1. | 2013 Sep 5 |
|
| Repairing of N-mustard derivative BO-1055 induced DNA damage requires NER, HR, and MGMT-dependent DNA repair mechanisms. | 2015 Sep 22 |
|
| In vitro and in vivo activity of melflufen (J1)in lymphoma. | 2016 Apr 4 |
|
| A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. | 2016 Aug |
|
| In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia. | 2017 Jan 24 |
|
| Melflufen - a peptidase-potentiated alkylating agent in clinical trials. | 2017 Sep 12 |
Patents
Sample Use Guides
Phase 3 clinical study (OCEAN, OP-103). Melflufen 40 mg i.v. on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle.
Route of Administration:
Intravenous
In Vitro Use Guide
Curator's Comment: RPMI-8226 (multiple myeloma) cells were treated with 10 uM or 100 uM of melphalan.
Melflufen showed activity with cytotoxic IC50-values in the submicromolar range (0.011-0.92 μM) in the cell lines. In the primary cultures melflufen yielded slightly lower IC50-values (2.7 nM to 0.55 μM). Treated cell lines exhibited a clear accumulation in the G2/M-phase of the cell cycle.
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465314
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C175815
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GH-115
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3412470A0V
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100000178184
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380449-54-7
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SUB193789
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70675838
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ACTIVE MOIETY
METABOLITE ACTIVE (PRODRUG)
SUBSTANCE RECORD
