Format

Send to

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

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

Author information

1
George Mason University, Department of Chemistry and Biochemistry, 10900 University Blvd, MS 1A9, Manassas, VA 20110, USA; Georgetown University Medical Center, Center for Drug Discovery, 3970 Reservoir Road, NW, The Research Building, Room EP07, Washington, DC 20057, USA. Electronic address: mpaige3@gmu.edu.
2
Georgetown University Medical Center, Center for Drug Discovery, 3970 Reservoir Road, NW, The Research Building, Room EP07, Washington, DC 20057, USA.
3
Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, 3970 Reservoir Road, NW, The Research Building, Washington, DC 20057, USA; Bahcesehir University, Faculty of Arts and Sciences, Department of Genetics and Bioinformatics, Besiktas, Istanbul 34349, Turkey.
4
Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, 3970 Reservoir Road, NW, The Research Building, Washington, DC 20057, USA.
5
Georgetown University Medical Center, Center for Drug Discovery, 3970 Reservoir Road, NW, The Research Building, Room EP07, Washington, DC 20057, USA; Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, 3970 Reservoir Road, NW, The Research Building, Washington, DC 20057, USA.
6
Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, 3970 Reservoir Road, NW, The Research Building, Washington, DC 20057, USA. Electronic address: au26@georgetown.edu.

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

PMID:
24326277
PMCID:
PMC4349528
DOI:
10.1016/j.bmc.2013.11.003
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center