Synthesis and Biological Evaluation of Analogues of the Potent ADAM8 Inhibitor cyclo(RLsKDK) for the Treatment of Inflammatory Diseases and Cancer Metastasis

Bioorg Med Chem. 2016 Sep 15;24(18):4032-4037. doi: 10.1016/j.bmc.2016.06.042. Epub 2016 Jun 23.

Abstract

The metalloproteinase ADAM8 serves as a pivotal catalyst in the development of inflammatory diseases and cancer metastasis. The cyclic peptide cyclo(RLsKDK) has been shown to inhibit the enzymatic activity of ADAM8 with high specificity and potency. Herein we report a structure-activity relationship (SAR) study of cyclo(RLsKDK) that involves the synthesis and biological evaluation of the lead compound and structural analogues thereof. This study provides insight into the ligand-receptor interactions that govern the binding of cyclo(RLsKDK) to the ADAM8 disintegrin domain and represents a stepping stone for the development of new treatments for inflammatory diseases and cancer metastasis.

Keywords: ADAM8 inhibitors; Cancer metastasis; Cyclic peptides; Peptidomimetics; SAR study.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAM Proteins / immunology
  • Animals
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / pharmacology*
  • COS Cells
  • Chlorocebus aethiops
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / immunology
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / immunology
  • Neoplasm Metastasis / drug therapy*
  • Neoplasm Metastasis / immunology
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / pharmacology*
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Membrane Proteins
  • Peptides, Cyclic
  • Peptidomimetics
  • ADAM Proteins
  • ADAM8 protein, human