Abstract
The oncofetal mRNA-binding protein, IMP1 or insulin-like growth factor-2 mRNA-binding protein 2 (IGF2BP1), binds to and stabilizes c-Myc, β-TrCP1, and other oncogenic mRNAs, leading to increased expression of the proteins encoded by its target mRNAs. IMP1 is frequently overexpressed in cancer and is strongly correlated with a poor prognosis and reduced survival in melanoma, ovarian, breast, colon, and lung cancer. While IMP1 is an attractive anticancer drug target, there are no small molecule inhibitors of IMP1. A fluorescence anisotropy-based assay was used to screen 160,000 small molecules for their ability to inhibit IMP1 binding to fluorescein-labeled c-Myc mRNA. The small molecule, BTYNB, was identified as a potent and selective inhibitor of IMP1 binding to c-Myc mRNA. In cells, BTYNB downregulates several mRNA transcripts regulated by IMP1. BTYNB destabilizes c-Myc mRNA, resulting in downregulation of c-Myc mRNA and protein. BTYNB downregulates β-TrCP1 mRNA and reduces activation of nuclear transcriptional factors-kappa B (NF-κB). The oncogenic translation regulator, eEF2, emerged as a new IMP1 target mRNA, enabling BTYNB to inhibit tumor cell protein synthesis. BTYNB potently inhibited proliferation of IMP1-containing ovarian cancer and melanoma cells with no effect in IMP1-negative cells. Overexpression of IMP1 reversed BTYNB inhibition of cell proliferation. BTYNB completely blocked anchorage-independent growth of melanoma and ovarian cancer cells in colony formation assays. With its ability to target c-Myc and to inhibit proliferation of difficult-to-target melanomas and ovarian cancer cells, and with its unique mode of action, BTYNB is a promising small molecule for further therapeutic evaluation and mechanistic studies.