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

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.

Characterization of Anti-Cancer Activities of Violacein: Actions on Tumor Cells and the Tumor Microenvironment

“…To test whether violacein affects normal cells to the same extent, we used a model of long-term cultivation of Huh7 in human serum. The transition of the cell line towards a more normal, hepatocyte-like phenotype has been demonstrated previously ( 25 , 26 ). In this model, the activity of violacein was abolished ( Figure 1B ).…”

“…Huh7 cells were differentiated in 2% human serum (PAN-Biotech #P40-2701) for three weeks, as described previously ( 25 , 26 ).…”

RNA m6A reader IGF2BP3 promotes metastasis of triple‐negative breast cancer via SLIT2 repression

“…These studies will be beneficial to assess whether IGF2BP3 can be targeted, e.g., by a decoy RNA or inhibitors, for the treatment of aggressive cancer. 31,32 Finally, while the present study focused on IGF2BP3, the IGF2BP family member that functions specifically in TNBC, it is worth to explore whether and how IGF2BP2 plays distinct roles in different subgroups of breast cancer. Since small molecule inhibitors for the components in the m6A methylation machinery are currently available, our findings hold out promise for development of novel therapeutics for clinical TNBC.…”

Beyond the approved: target sites and inhibitors of bacterial RNA polymerase from bacteria and fungi

“…462 In 2022, Dahlem et al reported that several ureidothiophene compounds target the RNA binding protein IGF2BP2/IMP2 [insulin-like growth factor 2 (IGF2) mRNA binding protein], which might be an interesting target in colorectal cancer therapy. 463…”

“…6B) inhibit the viral non-nucleoside reverse transcriptase of HIV-1 strains. 108 463 3.6.2. Sigma factor interaction inhibitorssummary and perspective.…”