Development of a specific and potent IGF2BP1 inhibitor: A promising therapeutic agent for IGF2BP1-expressing cancers

• Published in: European journal of medicinal chemistry Vol. 263; p. 115940
• Main Authors: Singh, Amandeep, Singh, Vikash, Wallis, Nadav, Abis, Giancarlo, Oberman, Froma, Wood, Tyler, Dhamdhere, Mayura, Gershon, Tehila, Ramos, Andres, Yisraeli, Joel, Spiegelman, Vladimir S., Sharma, Arun K.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier 05.01.2024
• Subjects: Animals; Cell Line, Tumor; Cell Movement; Chemistry, Medicinal; Gene Expression Regulation, Neoplastic; Life Sciences & Biomedicine; Neoplasms - drug therapy; Neoplasms - genetics; Pharmacology & Pharmacy; Science & Technology; BETA-TRCP1; Wound healing; IMPS; 15 N-HSQC; RNA-BINDING-PROTEIN; CRD-BP; OVEREXPRESSION; MESSENGER-RNA; Structure-activity relationship; CODING REGION; GROWTH; IGF2BP1; High-throughput screen; INDOLE-3-CARBINOL; EXPRESSION; N-HSQC
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115940

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.