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Development of a specific and potent IGF2BP1 inhibitor: A promising therapeutic agent for IGF2BP1-expressing cancers
Amandeep Singh1, Vikash Singh2, Nadav Wallis3
1The Pennsylvania State University College of Medicine, Department of Pharmacology, Penn State Cancer Institute, Hershey, PA, USA.
Abstract:
IGF2BP1 is a protein that controls the stability, localization, and translation of various mRNA targets. Poor clinical outcomes in numerous cancer types have been associated with its overexpression. As it has been demonstrated to impede tumor growth and metastasis in animal models, inhibiting IGF2BP1 function is a promising strategy for combating cancer. A lead chemical, 7773, which specifically decreased IGF2BP1 RNA binding and cellular activities, was previously identified in a high-throughput screen for effective IGF2BP1 inhibitors. Additional optimization of 7773 described in this manuscript led to the discovery of six compounds that performed equally well or better than 7773. In cell lines with high levels of endogenous IGF2BP1, one of 7773 derivatives, AVJ16, was found to be most efficient at preventing cell migration. Further, AVJ16 was found to be IGF2BP1-specific because it had no effect on cell lines that expressed little or no IGF2BP1 protein. The direct binding of AVJ16 to IGF2BP1 was validated by binding tests, with a 12-fold increase in binding efficiency over the lead compound. AVJ16 was shown to bind to a hydrophobic region at the protein's KH34 di-domain interface between the KH3 and KH4 domains. Overall, the findings imply that AVJ16 is a potent and specific inhibitor of IGF2BP1 activity.
Insights
Researchers developed AVJ16, a potent and specific inhibitor targeting Insulin-like Growth Factor 2 mRNA-binding Protein 1 (IGF2BP1). This new compound effectively blocks cancer cell migration by inhibiting IGF2BP1 activity, offering a promising cancer treatment strategy.
Area of Science:
- Molecular Biology
- Oncology
- Drug Discovery
Background:
- Insulin-like Growth Factor 2 mRNA-binding Protein 1 (IGF2BP1) overexpression is linked to poor cancer outcomes.
- IGF2BP1 inhibition shows potential for impeding tumor growth and metastasis.
- A lead compound, 7773, was identified as an IGF2BP1 inhibitor.
Purpose of the Study:
- To optimize the lead compound 7773 for enhanced IGF2BP1 inhibition.
- To discover novel, potent, and specific IGF2BP1 inhibitors.
- To evaluate the efficacy and specificity of optimized compounds in cancer models.
Main Methods:
- Chemical optimization of the lead compound 7773.
- Cell-based assays to assess inhibition of cell migration.
- Specificity testing in cell lines with varying IGF2BP1 expression levels.
- Biochemical assays to validate direct binding to IGF2BP1.
Main Results:
- Six optimized compounds demonstrated equal or superior performance to 7773.
- AVJ16, a derivative of 7773, was the most effective inhibitor of cancer cell migration in IGF2BP1-high cell lines.
- AVJ16 exhibited IGF2BP1 specificity, with no effect on cell lines lacking IGF2BP1.
- AVJ16 showed a 12-fold increase in binding efficiency to IGF2BP1 compared to the lead compound.
- AVJ16 binds to a hydrophobic region within the KH3-KH4 domain interface of IGF2BP1.
Conclusions:
- AVJ16 is a highly potent and specific inhibitor of IGF2BP1.
- AVJ16 represents a promising therapeutic candidate for cancers driven by IGF2BP1.
- Targeting IGF2BP1 with specific inhibitors like AVJ16 is a viable strategy for cancer therapy.
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