A Novel IMP1 Inhibitor, BTYNB, Targets c-Myc and Inhibits Melanoma and Ovarian Cancer Cell Proliferation

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.

Grifolin, neogrifolin and confluentin from the terricolous polypore Albatrellus flettii suppress KRAS expression in human colon cancer cells

“…To our knowledge, this is the first description of a small molecule inhibiting IMP1-KRAS RNA interaction. A small molecule called BTYNB has been reported to inhibit IMP1-c-myc RNA interaction [46]. The present study raises the possibility that confluentin suppresses KRAS expression by disrupting IMP1-KRAS mRNA in colon cancer cells.…”

Trophectoderm-Specific Knockdown of LIN28 Decreases Expression of Genes Necessary for Cell Proliferation and Reduces Elongation of Sheep Conceptus

“…Our results show that RNAi of LIN28A or LIN28B and resultant increase in let-7 miRNAs in day 16 TE significantly reduced IGF2BP1, IGF2BP2, IGF2BP3, HMGA1, ARID3B, and c-MYC. Previous studies have shown the role of IGF2BP1, IGF2BP2, IGF2BP3, HMGA1, ARID3B, and c-MYC in cell proliferation [17,[38][39][40]43,45,46,48,51], suggesting that reduced proliferation of trophoblast cells after LIN28A or LIN28B knockdown in TE is due to reduced expression of proliferation-associated genes (Figure 12). To further investigate the role of the LIN28-let-7 miRNA axis in sheep trophoblast cells in vitro, OTR cells were generated from day 16 TE.…”

“…By binding different mRNAs, IGF2BPs decide the fate of those mRNAs by controlling their localization, stability, and translation [40]. Many studies have reported the role of IGF2BPs in cell proliferation, cell invasion, tumorigenesis, and embryogenesis [40][41][42][43][44][45][46][47][48][49][50][51]. IGF2BPs have also been found in sheep trophoblast cells suggesting their role in rapid proliferation of these cells [52].…”

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in cancer

“…BTYNB may restrain binding of IGF2BP1 to the coding region stability determinant of c-Myc mRNA and downregulate several mRNA transcripts including c-Myc, β-TrCP1, and eEF2 both in IGROV-1 and SK-MEL2 cancer cells, as well as decrease activation of nuclear transcriptional factors-kappa B (NF-κB). Moreover, it also selectively reduces the levels of other cancer-related IGF2BP1 mRNA targets including CALM1, CDC34, COL5A, and BTRC, similar to the effect by RNAi knockdown of IGF2BP1 both in IGROV-1 and SK-MEL2 cancer cells [ 104 ].…”