PUBLICATION
Identification of novel ezrin inhibitors targeting metastatic osteosarcoma by screening open access malaria box
- Authors
- Celik, H., Hong, S.H., Colón-López, D.D., Han, J., Saygideger Kont, Y., Minas, T.Z., Swift, M., Paige, M., Glasgow, E., Toretsky, J.A., Bosch, J., Uren, A.
- ID
- ZDB-PUB-150912-6
- Date
- 2015
- Source
- Molecular cancer therapeutics 14(11): 2497-507 (Journal)
- Registered Authors
- Glasgow, Eric, Swift, Matthew Russell
- Keywords
- none
- MeSH Terms
-
- Adamantane/analogs & derivatives*
- Adamantane/pharmacology
- Animals
- Antimalarials/pharmacology
- Antineoplastic Agents/pharmacology*
- Cell Line, Tumor
- Cell Movement/drug effects
- Cell Survival/drug effects
- Cytoskeletal Proteins/antagonists & inhibitors*
- Cytoskeletal Proteins/metabolism
- Drug Evaluation, Preclinical/methods
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/embryology
- Embryo, Nonmammalian/metabolism
- Immunoblotting
- Lung Neoplasms/prevention & control
- Lung Neoplasms/secondary
- Mice, Inbred BALB C
- Osteosarcoma/drug therapy*
- Osteosarcoma/metabolism
- Osteosarcoma/pathology
- Quinolines/pharmacology*
- Small Molecule Libraries/pharmacology
- Surface Plasmon Resonance
- Zebrafish/embryology
- Zebrafish/metabolism
- PubMed
- 26358752 Full text @ Mol. Cancer Ther.
Citation
Celik, H., Hong, S.H., Colón-López, D.D., Han, J., Saygideger Kont, Y., Minas, T.Z., Swift, M., Paige, M., Glasgow, E., Toretsky, J.A., Bosch, J., Uren, A. (2015) Identification of novel ezrin inhibitors targeting metastatic osteosarcoma by screening open access malaria box. Molecular cancer therapeutics. 14(11):2497-507.
Abstract
Ezrin is a member of the ERM (ezrin, radixin, moesin) family of proteins and functions as a linker between the plasma membrane and the actin cytoskeleton. Ezrin is a key driver of tumor progression and metastatic spread of osteosarcoma. We discovered a quinoline-based small molecule, NSC305787 that directly binds to ezrin and inhibits its functions in promoting invasive phenotype. NSC305787 possesses a very close structural similarity to commonly used quinoline-containing antimalarial drugs. On the basis of this similarity and of recent findings that ezrin has a likely role in the pathogenesis of malaria infection, we screened antimalarial compounds in an attempt to identify novel ezrin inhibitors with better efficacy and drug properties. Screening of Medicines for Malaria Venture (MMV) Malaria Box compounds for their ability to bind to recombinant ezrin protein yielded 12 primary hits with high selective binding activity. The specificity of the hits on ezrin function was confirmed by inhibition of the ezrin-mediated cell motility of osteosarcoma cells. Compounds were further tested for phenocopying the morphological defects associated with ezrin suppression in zebrafish embryos as well as for inhibiting the lung metastasis of high ezrin-expressing osteosarcoma cells. The compound MMV667492 exhibited potent anti-ezrin activity in all biological assays and had better physicochemical properties for druglikeness than NSC305787. The drug-like compounds MMV020549 and MMV666069 also showed promising activities in functional assays. Thus, our study suggests further evaluation of antimalarial compounds as a novel class of anti-metastatic agents for the treatment of metastatic osteosarcoma.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping