Mechanism of action

The melflufen MoA Story

Melflufen is a lipophilic peptide-conjugated alkylator that rapidly delivers a highly cytotoxic payload into myeloma cells through peptidase activity. It belongs to the novel class Peptidase Enhanced Cytotoxics (PEnC), which is a family of lipophilic peptides that exhibit increased activity via peptidase cleavage and have the potential to treat many cancers.

  • Peptidases are expressed in several cancers, including solid tumors and hematologic malignancies.6-8
  • Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity.1,3
  • Once inside the myeloma cell, the activity of melflufen is determined by its immediate cleavage by peptidases into hydrophilic alkylator payloads that are entrapped.3-5
  • Melflufen is 50-fold more potent than melphalan in myeloma cells in vitro due to the increase of intracellular alkylator activity.1,3
  • Meflufen rapidly induces irreversible DNA damage leading to apoptosis of myeloma cells.1,2
  • Melflufen displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, in vitro.1,2
  • Melflufen also has demonstrated inhibition of angiogenesis and induction of DNA damage with a lack of functional DNA repair in preclinical studies.1,2,9

 

  1. Chauhan D, Ray A, Viktorsson K, et al. In vitro and In vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells. Clinical Cancer Research. 2013;19(11):3019-3031.
  2. Ray A, Ravillah D, Das DS, et al. A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. British Journal of Haematology. 2016;174(3):397-409.
  3. Wickström M, Nygren P, Larsson R, et al. Melflufen – a peptidase-potentiated alkylating agent in clinical trials. Oncotarget. 2017;8(39).
  4. Wickström M, Viktorsson K, Lundholm L, et al. The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a possible target directed release of melphalan. Biochemical Pharmacology. 2010;79(9):1281-1290.
  5. Gullbo J, Wickström M, Tullberg M, et al. Activity of hydrolytic enzymes in tumour cells is a determinant for anti-tumour efficacy of the melphalan containing prodrugJ1. Journal of Drug Targeting. 2003;11(6):355-363.
  6. Hitzerd SM, Verbrugge SE, Ossenkoppele G, Jansen G, Peters GJ. Positioning of aminopeptidase inhibitors in next generation cancer therapy. Amino Acids. 2014;46(4):793-808.
  7. Moore HE, Davenport EL, Smith EM, et al. Aminopeptidase inhibition as a targeted treatment strategy in myeloma. Molecular Cancer Therapeutics. 2009;8(4):762-770.
  8. Wickström M, Larsson R, Nygren P, Gullbo J. Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Science. 2011;102(3):501-508.
  9. Strese S, Wickström M, Fuchs PF, et al. The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo. Biochemical Pharmacology. 2013;86(7):888-895.