2. Academic Validation
  3. First Small-Molecule Inhibitors Targeting the RNA-Binding Protein IGF2BP2/IMP2 for Cancer Therapy

First Small-Molecule Inhibitors Targeting the RNA-Binding Protein IGF2BP2/IMP2 for Cancer Therapy

  • ACS Chem Biol. 2022 Feb 18;17(2):361-375. doi: 10.1021/acschembio.1c00833.
Charlotte Dahlem 1,  Ali Abuhaliema 1,  Sonja M Kessler 1 2,  Tarek Kröhler 1,  Ben G E Zoller 3,  Shilpee Chanda 1,  Yingwen Wu 3,  Simon Both 1,  Fabian Müller 4,  Konstantin Lepikhov 5,  Susanne H Kirsch 6,  Stephan Laggai 1,  Rolf Müller 6 7,  Martin Empting 3 7,  Alexandra K Kiemer 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken 66123, Germany.
  • 2 Institute of Pharmacy, Experimental Pharmacology for Natural Sciences, Martin Luther University Halle-Wittenberg, Halle 06108, Germany.
  • 3 Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University, Saarbrücken 66123, Germany.
  • 4 Center for Bioinformatics, Saarland University, Saarbrücken 66123, Germany.
  • 5 Department of Genetics, Saarland University, Saarbrücken 66123, Germany.
  • 6 Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University, Saarbrücken 66123, Germany.
  • 7 Department of Pharmacy, Saarland University, Saarbrücken 66123, Germany.
PMID: 35023719 DOI: 10.1021/acschembio.1c00833
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.

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