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

Area of Science:

• Molecular Biology
• Oncology
• Drug Discovery

Background:

• Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is frequently overexpressed in various cancers, correlating with poor patient outcomes.
• IGF2BP2 plays a significant role in promoting tumorigenesis and cancer progression.

Purpose of the Study:

• To validate IGF2BP2 as a druggable target in colorectal cancer.
• To develop a screening assay for small-molecule inhibitors of IGF2BP2.
• To evaluate the biological activity of identified IGF2BP2 inhibitors.

Main Methods:

• Analysis of cancer gene expression data to correlate IGF2BP2 levels with patient survival.
• In vitro validation using 2D and 3D cell cultures with IGF2BP2 knockout cells.
• In vivo validation in xenotransplant models and zebrafish embryos.
• High-throughput screening using fluorescence polarization assays, confirmed by thermal shift assay and NMR.

Main Results:

• High IGF2BP2 expression is linked to reduced survival in colorectal and liver cancer patients, particularly in advanced stages.
• IGF2BP2 knockout cells exhibited decreased viability, migration, and proliferation in vitro, and reduced tumor growth in vivo.
• Screening identified ten validated small-molecule inhibitors of IGF2BP2, belonging to benzamidobenzoic acid and ureidothiophene classes.
• The most potent compounds demonstrated reduced tumor xenograft growth in zebrafish embryos.

Conclusions:

• IGF2BP2 is a validated druggable target for cancer therapy.
• Small-molecule inhibitors targeting IGF2BP2 show significant anti-tumor activity.
• Targeting IGF2BP2 offers a promising strategy to reduce tumor cell proliferation and improve cancer treatment outcomes.