title: Design, synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma.
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.
authors: 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.
authors: Mikell
authors: M
authors: Paige
authors: Georgetown University Medical Center, Center for Drug Discovery, 3970 Reservoir Road, NW, The Research Building, Room EP07, Washington, DC 20057, USA.
authors: George
authors: G
authors: Kosturko
authors: 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.
authors: Güllay
authors: G
authors: Bulut
authors: Georgetown University Medical Center, Center for Drug Discovery, 3970 Reservoir Road, NW, The Research Building, Room EP07, Washington, DC 20057, USA.
authors: Matthew
authors: M
authors: Miessau
authors: Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, 3970 Reservoir Road, NW, The Research Building, Washington, DC 20057, USA.
authors: Said
authors: S
authors: Rahim
authors: Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, 3970 Reservoir Road, NW, The Research Building, Washington, DC 20057, USA.
authors: Jeffrey A
authors: JA
authors: Toretsky
authors: 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.
authors: Milton L
authors: ML
authors: Brown
authors: Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, 3970 Reservoir Road, NW, The Research Building, Washington, DC 20057, USA. Electronic address: au26@georgetown.edu.
authors: Aykut
authors: A
authors: Üren
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000138:chemical synthesis*; D015195:Drug Design; D006801:Humans; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D000099149:Ezrin
chemical_list: D000970:Antineoplastic Agents; D003598:Cytoskeletal Proteins; D000099149:Ezrin
keywords: Chemotaxis; Ezrin; Metastasis; Osteosarcoma