MELPHALAN FLUFENAMIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C24H30Cl2FN3O3
Molecular Weight	498.4185
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCOC(=O)[C@]([H])(Cc1ccc(cc1)F)N=C([C@]([H])(Cc2ccc(cc2)N(CCCl)CCCl)N)O

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	498.4185
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/

Melphalan flufenamide ethyl ester (melflufen, previously denoted J1) is a peptidase-potentiated dipeptide prodrug of alkylating agent melphalan. Melflufen readily penetrates membranes and an equilibrium is rapidly achieved, followed by enzymatic cleavage in aminopeptidase positive cells, which results in trapping of less lipophilic metabolites. This targeting effect results in very high intracellular concentrations of its metabolite melphalan and subsequent apoptotic cell death. This results in a potency increase (melflufen vs melphalan) ranging from 10- to several 100-fold in different in vitro models. Melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in multiple myeloma cells. Melflufen has been granted orphan drug designation for the treatment of multiple myeloma.

Originator

Approval Year

PubMed

Title	Date	PubMed
In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells.	2013 Jun 1	23584492
The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo.	2013 Oct 1	23933387
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
In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia.	2017 Jan 24	27974676
Melflufen - a peptidase-potentiated alkylating agent in clinical trials.	2017 Sep 12	29029544

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 Jun 25 23:17:09 UTC 2021` Edited by `admin` on `Fri Jun 25 23:17:09 UTC 2021`
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 J 1

Code

English

J-1

Code

English

J1

Code

English

MFF

Common Name

English

MELPHALAN FLUFENAMIDE [INN]

Common Name

English

J 1 (PRODRUG)

Code

English

J-1 (PRODRUG)

Code

English

MELPHALAN FLUFENAMIDE [USAN]

Common Name

English

MELPHALAN FLUFENAMIDE [WHO-DD]

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