MELPHALAN FLUFENAMIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C24H30Cl2FN3O3
Molecular Weight	498.418
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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=YQZNKYXGZSVEHI-VXKWHMMOSA-N

InChI=1S/C24H30Cl2FN3O3/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)/t21-,22-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C24H30Cl2FN3O3
Molecular Weight	498.418
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 278 Target ID: CHEMBL2311221 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdf	Crosslinking Agent 81

Conditions

Condition	Modality	Targets	Highest Phase	Product
Multiple myeloma 159 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdf	Palliative		Approved 8429	ALKERAN Approved Use ALKERAN Tablets are indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Launch Date 1964
Epithelial carcinoma of the ovary 4 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s029lbl.pdf	Palliative		Approved 8429	ALKERAN Approved Use ALKERAN Tablets are indicated for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Launch Date 1964

C_max

Value	Dose	Co-administered	Analyte	Population
212 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s030lbl.pdf	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 DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s030lbl.pdf	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
1 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/014691s030lbl.pdf	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

F_unbound

Value	Dose	Co-administered	Analyte	Population
70% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207155s000lbl.pdf			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: https://pubmed.ncbi.nlm.nih.gov/10656432 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: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60	DLT: Thrombocytopenia, Neutropenia... Dose limiting toxicities: Thrombocytopenia (grade 4, 57%) Neutropenia (grade 4, 57%) Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60
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: https://pubmed.ncbi.nlm.nih.gov/10656432 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: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60	DLT: Thrombocytopenia, Neutropenia... Dose limiting toxicities: Thrombocytopenia (grade 4, 44%) Neutropenia (grade 4, 44%) Sources: https://pubmed.ncbi.nlm.nih.gov/10656432 Page: p.60
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: https://pubmed.ncbi.nlm.nih.gov/9720737 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: https://pubmed.ncbi.nlm.nih.gov/9720737 Page: p.248, 250	Disc. AE: Toxic reaction (NOS), Bacterial infection... AEs leading to discontinuation/dose reduction: Toxic reaction (NOS) (grade 4, 1.8%) Bacterial infection (grade 5, 3.6%) Systemic herpes zoster infection (grade 5, 1.8%) Sources: https://pubmed.ncbi.nlm.nih.gov/9720737 Page: p.248, 250
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207155s000lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Multiple myeloma Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207155s000lbl.pdf Page: p.1	Disc. AE: Bone marrow depression, Hypersensitivity reaction... AEs leading to discontinuation/dose reduction: Bone marrow depression (severe) Hypersensitivity reaction (2%) Anaphylaxis Gastrointestinal toxicity Nausea Vomiting Diarrhea Mucositis oral Fetal damage Infertility Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207155s000lbl.pdf Page: p.1

AEs

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:28876	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:28876
ChemicalBook	CB2492687	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2492687
MolPort	MolPort-003-665-535	https://www.molport.com/shop/molecule-link/MolPort-003-665-535
ZINC	ZINC000000001673	http://zinc15.docking.org/substances/ZINC000000001673
eMolecules	525665	https://www.emolecules.com/cgi-bin/more?vid=525665

PubMed

Title	Date	PubMed
Lymphocyte transformation studies in drug hypersensitivity.	1979 May 5	445303
Interaction of melphalan and dexamethasone in a human myeloma cell line.	1991 Dec	1806033
Multiple myeloma with coexistent myelofibrosis: improvement of myelofibrosis following recovery from multiple myeloma after treatment with melphalan and prednisolone.	1991 Sep-Oct	1803051
Deletion 5q31 in patients with stable, melphalan-treated multiple myeloma.	1999 Aug	10459345
Absence of severe systemic toxicity after leakage-controlled isolated limb perfusion with tumor necrosis factor-alpha and melphalan.	1999 Jun	10379864
Genomic cloning and characterization of the rat glutathione S-transferase-A3-subunit gene.	1999 May 1	10215608
Myeloblastoma (chloroma) in leukemia: case 2. Meningeal granulocytic sarcoma (chloroma) in essential thrombocythemia.	2000 Dec 1	11099330
A phase I and pharmacokinetic study of melphalan using a 24-hour continuous infusion in patients with advanced malignancies.	2000 Jan	10656432
Acute left ventricular failure following melphalan and fludarabine conditioning.	2001 Jul	11498753
Cytotoxic N-[4-(3-aryl-3-oxo-1-propenyl)phenylcarbonyl]-3,5-bis(phenylmethylene)-4-piperidones and related compounds.	2002 Dec	12660021
Deletion of 5q31 and 7q31 in patients with stable melphalan treated multiple myeloma.	2004 Jul 1	15193449
The nitrogen mustard melphalan activates mitogen-activated phosphorylated kinases (MAPK), nuclear factor-kappaB and inflammatory response in lung epithelial cells.	2005 Jul-Aug	16025434
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor.	2005 Oct 15	16243825
Bortezomib-dexamethasone combination in a patient with refractory multiple myeloma and impaired renal function.	2006 Jun	16860177
Hypercalcemia induced by 13 cis-retinoic acid in patients with neuroblastoma.	2008 Apr	18353067
Pharmacologic profiling of human and rat cytochrome P450 1A1 and 1A2 induction and competition.	2008 Dec	18493746
Cytogenetically defined myelodysplasia after melphalan-based autotransplantation for multiple myeloma linked to poor hematopoietic stem-cell mobilization: the Arkansas experience in more than 3,000 patients treated since 1989.	2008 Jan 1	17895401
Heterogeneity of human glioblastoma: glutathione-S-transferase and methylguanine-methyltransferase.	2008 Jul	18584351
Cardiac toxicity of high-dose cyclophosphamide and melphalan in patients with multiple myeloma treated with tandem autologous hematopoietic stem cell transplantation.	2008 Sep	18548196
Excessive toxicity of once daily i.v. BU, melphalan and thiotepa followed by auto SCT on patients with non-Hodgkin's lymphoma.	2010 Apr	19767780
Efficacy and safety of once-weekly bortezomib in multiple myeloma patients.	2010 Dec 2	20807892
Thalidomide-induced phrenic nerve paralysis.	2010 Feb	20038224
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	20864405
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	20874823
Bone marrow osteoblast damage by chemotherapeutic agents.	2012	22363485
In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells.	2013 Jun 1	23584492
FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-1.	2013 Sep 5	23769903
In vitro and in vivo activity of melflufen (J1)in lymphoma.	2016 Apr 4	27044263
A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells.	2016 Aug	27098276

Patents

Sample Use Guides

In Vivo Use Guide

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

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.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 20:15:37 GMT 2023` Edited by `admin` on `Fri Dec 15 20:15:37 GMT 2023`
Record UNII	F70C5K4786
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

MELPHALAN FLUFENAMIDE

Official Name

English

L-PHENYLALANINE, 4-(BIS(2-CHLOROETHYL)AMINO)-L-PHENYLALANYL-4-FLUORO-, ETHYL ESTER

Systematic Name

English

PRODRUG J1

Code

English

J-1

Code

English

Melphalan flufenamide [WHO-DD]

Common Name

English

J1

Code

English

MFF

Common Name

English

melphalan flufenamide [INN]

Common Name

English

J1 (PRODRUG)

Code

English

J-1 (PRODRUG)

Code

English

MELPHALAN FLUFENAMIDE [USAN]

Common Name

English

ETHYL (2S)-2-((2S)-2-AMINO-3-(4-(BIS(2-CHLOROETHYL)AMINO)PHENYL)PROPANAMIDO)-3-(4-FLUOROPHENYL)PROPANOATE

Systematic Name

English

PRODRUG J-1

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C697