Novel crizotinib–gnrh conjugates revealed the significance of lysosomal trapping in gnRH-based drug delivery systems

József Murányi, Attila Varga, Pál Gyulavári, Kinga Pénzes, Csilla E. Németh, Miklós Csala, Lilla Pethő, Antal Csámpai, Gábor Halmos, István Peták, István Vályi-Nagy

Research output: Contribution to journalArticle


Several promising anti-cancer drug–GnRH (gonadotropin-releasing hormone) conjugates have been developed in the last two decades, although none of them have been approved for clinical use yet. Crizotinib is an effective multi-target kinase inhibitor, approved against anaplastic lymphoma kinase (ALK)-or ROS proto-oncogene 1 (ROS-1)-positive non-small cell lung carcinoma (NSCLC); however, its application is accompanied by serious side effects. In order to deliver crizotinib selectively into the tumor cells, we synthesized novel crizotinib analogues and conjugated them to a [D-Lys6]–GnRH-I targeting peptide. Our most prominent crizotinib–GnRH conjugates, the amide-bond-containing [D-Lys6(crizotinib*)]–GnRH-I and the ester-bond-containing [D-Lys6(MJ55*)]–GnRH-I, were able to bind to GnRH-receptor (GnRHR) and exert a potent c-Met kinase inhibitory effect. The efficacy of compounds was tested on the MET-amplified and GnRHR-expressing EBC-1 NSCLC cells. In vitro pharmacological profiling led to the conclusion that that crizotinib–GnRH conjugates are transported directly into lysosomes, where the membrane permeability of crizotinib is diminished. As a consequence of GnRHR-mediated endocytosis, GnRH-conjugated crizotinib bypasses its molecular targets—the ATP-binding site of RTKs— and is sequestered in the lysosomes. These results explained the lower efficacy of crizotinib–GnRH conjugates in EBC-1 cells, and led to the conclusion that drug escape from the lysosomes is a major challenge in the development of clinically relevant anti-cancer drug–GnRH conjugates.

Original languageEnglish
Article number5590
JournalInternational journal of molecular sciences
Issue number22
Publication statusPublished - Nov 2 2019


  • C-Met 8
  • Conjugate 6
  • Crizotinib 5
  • Endocytosis 9
  • Galectin 10
  • GnRH 2
  • GnRHR 3
  • Lysosome 3
  • NSCLC 7
  • Permeability 4
  • Targeted drug delivery 1

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint Dive into the research topics of 'Novel crizotinib–gnrh conjugates revealed the significance of lysosomal trapping in gnRH-based drug delivery systems'. Together they form a unique fingerprint.

  • Cite this