Please use this identifier to cite or link to this item: doi:10.22028/D291-37440
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Title: First Small-Molecule Inhibitors Targeting the RNA-Binding Protein IGF2BP2/IMP2 for Cancer Therapy
Author(s): Dahlem, Charlotte
Abuhaliema, Ali
Kessler, Sonja M.
Kröhler, Tarek
Zoller, Ben G. E.
Chanda, Shilpee
Wu, Yingwen
Both, Simon
Müller, Fabian
Lepikhov, Konstantin
Kirsch, Susanne H.
Laggai, Stephan
Müller, Rolf
Empting, Martin
Kiemer, Alexandra K.
Language: English
Title: ACS Chemical Biology
Volume: 17
Issue: 2
Pages: 361-375
Publisher/Platform: ACS
Year of Publication: 2022
DDC notations: 500 Science
Publikation type: Journal Article
Abstract: The RNA-binding protein IGF2BP2/IMP2/VICKZ2/p62 is overexpressed in several tumor entities, promotes tumorigenesis and tumor progression, and has been suggested to worsen the disease outcome. The aim of this study is to (I) validate IMP2 as a potential target for colorectal cancer, (II) set up a screening assay for small-molecule inhibitors of IMP2, and (III) test the biological activity of the obtained hit compounds. Analyses of colorectal and liver cancer gene expression data showed reduced survival in patients with a high IMP2 expression and in patients with a higher IMP2 expression in advanced tumors. In vitro target validation in 2D and 3D cell cultures demonstrated a reduction in cell viability, migration, and proliferation in IMP2 knockout cells. Also, xenotransplant tumor cell growth in vivo was significantly reduced in IMP2 knockouts. Different compound libraries were screened for IMP2 inhibitors using a fluorescence polarization assay, and the results were confirmed by the thermal shift assay and saturation-transfer difference NMR. Ten compounds, which belong to two classes, that is, benzamidobenzoic acid class and ureidothiophene class, were validated in vitro and showed a biological target specificity. The three most active compounds were also tested in vivo and exhibited reduced tumor xenograft growth in zebrafish embryos. In conclusion, our findings support that IMP2 represents a druggable target to reduce tumor cell proliferation.
DOI of the first publication: 10.1021/acschembio.1c00833
URL of the first publication:
Link to this record: urn:nbn:de:bsz:291--ds-374408
ISSN: 1554-8937
Date of registration: 29-Sep-2022
Description of the related object: Supporting Information
Related object:
Faculty: NT - Naturwissenschaftlich- Technische Fakultät
Department: NT - Biowissenschaften
NT - Pharmazie
Professorship: NT - Prof. Dr. Anna Hirsch
NT - Prof. Dr. Alexandra K. Kiemer
NT - Prof. Dr. Rolf Müller
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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