Design, synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma

Bioorg Med Chem. 2014 Jan 1;22(1):478-87. doi: 10.1016/j.bmc.2013.11.003. Epub 2013 Nov 14.

Abstract

Respiratory failure due to pulmonary metastasis is the major cause of death for patients with osteosarcoma. However, the molecular basis for metastasis of osteosarcoma is poorly understood. Recently, ezrin, a member of the ERM family of proteins, has been associated with osteosarcoma metastasis to the lungs. The small molecule NSC 668394 was identified to bind to ezrin, inhibit in vitro and in vivo cell migration, invasion, and metastatic colony survival. Reported herein are the design and synthesis of analogues of NSC 668394, and subsequent functional ezrin inhibition studies. The binding affinity was characterized by surface plasmon resonance technique. Cell migration and invasion activity was determined by electrical cell impedance methodology. Optimization of a series of heterocyclic-dione analogues led to the discovery of compounds 21k and 21m as potential novel antimetastatic agents.

Keywords: Chemotaxis; Ezrin; Metastasis; Osteosarcoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Cytoskeletal Proteins / antagonists & inhibitors
  • Cytoskeletal Proteins / chemical synthesis*
  • Drug Design
  • Humans
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology

Substances

  • Antineoplastic Agents
  • Cytoskeletal Proteins
  • ezrin