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Design, synthesis, and biological studies of efficient multivalent melanotropin ligands: tools toward melanoma diagnosis and treatment.

Authors
  • Brabez, Nabila
  • Lynch, Ronald M
  • Xu, Liping
  • Gillies, Robert J
  • Chassaing, Gerard
  • Lavielle, Solange
  • Hruby, Victor J
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Oct 27, 2011
Volume
54
Issue
20
Pages
7375–7384
Identifiers
DOI: 10.1021/jm2009937
PMID: 21928837
Source
Medline
License
Unknown

Abstract

To achieve early detection and specific cancer treatment, we propose the use of multivalent interactions in which a series of binding events leads to increased affinity and consequently to selectivity. Using melanotropin (MSH) ligands, our aim is to target melanoma cells which overexpress melanocortin receptors. In this study, we report the design and efficient synthesis of new trivalent ligands bearing MSH ligands. Evaluation of these multimers on a cell model engineered to overexpress melanocortin 4 receptors (MC4R) showed up to a 350-fold increase in binding compared to the monomer, resulting in a trivalent construct with nanomolar affinity starting from a micromolar affinity ligand. Cyclic adenosine monophosphate (cAMP) production was also investigated, leading to more insights into the effects of multivalent compounds on transduction mechanisms.

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