Designer peptide antagonist of the leptin receptor with peripheral antineoplastic activity

Peptides. 2013 Jun;44:127-34. doi: 10.1016/j.peptides.2013.03.027. Epub 2013 Apr 6.


The obesity hormone leptin has been implicated in the development and progression of different cancer types, and preclinical studies suggest that targeting leptin signaling could be a new therapeutic option for the treatment of cancer, especially in obese patients. To inhibit pro-neoplastic leptin activity, we developed leptin receptor (ObR) peptide antagonists capable of blocking leptin effects in vitro and in vivo. Our lead compound (Allo-aca), however, crosses the blood-brain-barrier (BBB), inducing undesirable orexigenic effects and consequent weight gain. Thus, redesigning Allo-aca to uncouple its central and peripheral activities should produce a superior compound for cancer treatment. The aim of this study was to generate novel Allo-aca analogs and test their biodistribution in vivo and anti-neoplastic activity in vitro in breast and colorectal cancer cells. Examination of several Allo-aca analogs resulted in the identification of the peptidomimetic, d-Ser, that distributed only in the periphery of experimental animals. d-Ser inhibited leptin-dependent-proliferation of ObR-positive breast and colorectal cancer cells in vitro at 1nM concentration without exhibiting any partial agonistic activity. d-Ser efficacy was demonstrated in monolayer and three-dimensional cultures, and its antiproliferative action was associated with the inhibition of several leptin-induced pathways, including JAK/STAT3, MAPK/ERK1/2 and PI3K/AKT, cyclin D1, and E-cadherin. In conclusion, d-Ser is the first leptin-based peptidomimetic featuring peripheral ObR antagonistic activity. The novel peptide may serve as a prototype to develop new therapeutics, particularly for the management of obesity-related cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Female
  • HT29 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MCF-7 Cells
  • Mice
  • Mice, Inbred C57BL
  • Molecular Mimicry
  • Peptides / pharmacokinetics
  • Peptides / pharmacology*
  • Receptors, Leptin / antagonists & inhibitors*
  • Signal Transduction
  • Spheroids, Cellular / drug effects
  • Tissue Distribution
  • Weight Gain / drug effects


  • Antineoplastic Agents
  • D-Ser Allo-aca peptide
  • Intracellular Signaling Peptides and Proteins
  • Peptides
  • Receptors, Leptin