Identification of Novel Ezrin Inhibitors Targeting Metastatic Osteosarcoma by Screening Open Access Malaria Box

Celik Haydar; Hong Sung-Hyeok; Colon-Lopez Daisy D.; Han Jenny; Kont Yasemin Saygideger; Minas Tsion Z.; Swift Matthew; Paige Mikell; Glasgow Eric; Toretsky Jeffrey A.; Bosch Juergen; Ueren Aykut

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Identification of Novel Ezrin Inhibitors Targeting Metastatic Osteosarcoma by Screening Open Access Malaria Box

机译：通过筛选开放式疟疾盒鉴定靶向转移性骨肉瘤的新型Ezrin抑制剂

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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 morphologic 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 biologic assays and had better physicochemical properties for drug-likeness 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 antimetastatic agents for the treatment of metastatic osteosarcoma. (C) 2015 AACR.

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来源
《Molecular cancer therapeutics》 |2015年第11期|共11页
作者
Celik Haydar; Hong Sung-Hyeok; Colon-Lopez Daisy D.; Han Jenny; Kont Yasemin Saygideger; Minas Tsion Z.; Swift Matthew; Paige Mikell; Glasgow Eric; Toretsky Jeffrey A.; Bosch Juergen; Ueren Aykut;
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作者单位

Georgetown Univ Med Ctr Dept Oncol Washington DC 20057 USA;

Georgetown Univ Med Ctr Dept Oncol Washington DC 20057 USA;

Johns Hopkins Univ Bloomberg Sch Publ Hlth Dept Biochem &

Mol Biol Baltimore MD USA;

Georgetown Univ Med Ctr Dept Oncol Washington DC 20057 USA;

Georgetown Univ Med Ctr Dept Oncol Washington DC 20057 USA;

Georgetown Univ Med Ctr Dept Oncol Washington DC 20057 USA;

Georgetown Univ Med Ctr Dept Oncol Washington DC 20057 USA;

George Mason Univ Dept Chem &

Biochem Manassas VA USA;

Georgetown Univ Med Ctr Dept Oncol Washington DC 20057 USA;

Georgetown Univ Med Ctr Dept Oncol Washington DC 20057 USA;

Johns Hopkins Univ Bloomberg Sch Publ Hlth Johns Hopkins Malaria Res Inst Baltimore MD USA;

Georgetown Univ Med Ctr Dept Oncol Washington DC 20057 USA;

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原文格式 PDF
正文语种 eng
中图分类肿瘤学;
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6. Identification of Novel Ezrin Inhibitors Targeting Metastatic Osteosarcoma by Screening Open Access Malaria Box [J] . Celik Haydar, Hong Sung-Hyeok, Colon-Lopez Daisy D., Molecular cancer therapeutics . 2015,第11期

机译：通过筛选开放式疟疾盒鉴定靶向转移性骨肉瘤的新型Ezrin抑制剂
7. Design, synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma [J] . PaigeM., KosturkoG., BulutG., Bioorganic and medicinal chemistry . 2014,第1期

机译：针对转移性骨肉瘤的ezrin抑制剂的设计，合成及生物学评价
8. siRNAs target sites selection of ezrin and the influence of RNA interference on ezrin expression and biological characters of osteosarcoma cells. [J] . XiFu Shang, YaoFei Wang, QiChun Zhao, Molecular and Cellular Biochemistry: An International Journal for Chemical Biology . 2012,第1a2期

机译：siRNA靶向ezrin的位点选择以及RNA干扰对ezrin表达和骨肉瘤细胞生物学特性的影响。
9. Identification of Plasmodium falciparum thioredoxin reductase (PfTrxR) inhibitors from Malaria Box using LC-MS functional assay [C] . Angela I. Calderon, Neil Tiwari, Katja Becker ASMS Conference on Mass Spectrometry and Allied Topics . 2014

机译：使用LC-MS功能测定法鉴定来自疟疾盒的疟原虫氧化嗪（PFTRXR）抑制剂
10. IL-12 inhibits the metastatic potential of osteosarcoma cells and induces tumor regression via a mechanism involving Fas/Fas ligand pathway. [D] . Lafleur, Elizabeth Ann. 2003

机译：IL-12通过涉及Fas / Fas配体途径的机制抑制骨肉瘤细胞的转移潜能并诱导肿瘤消退。
11. Identification of novel ezrin inhibitors targeting metastatic osteosarcoma by screening open access malaria box [O] . Haydar Çelik, Sung-Hyeok Hong, Daisy D. Colón-López, -1

机译：通过筛选开放性疟疾框来鉴定靶向转移性骨肉瘤的新型ezrin抑制剂
12. Identification of Novel Ezrin Inhibitors Targeting Metastatic Osteosarcoma by Screening Open Access Malaria Box [O] . Haydar Çelik, Sung-Hyeok Hong, Daisy D. Colón-López, 2015

机译：通过筛选开放式疟疾盒鉴定靶向转移性骨肉瘤的新型Ezrin抑制剂
13. Targeting Mitochondrial Inhibitors for Metastatic Castrate-Resistant Prostate Cancer. [R] . Denmeade, S. 2017

机译：针对转移性去势抵抗前列腺癌靶向线粒体抑制剂。

Identification of Novel Ezrin Inhibitors Targeting Metastatic Osteosarcoma by Screening Open Access Malaria Box

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