Inhibitors of CRD-BP-KRAS RNA interaction

The KRAS mRNA is one of few oncogenic mRNAs that can be recognized and bound by the RNA-binding protein called Coding Region Determinant-Binding Protein (CRD-BP). Binding of CRD-BP to oncogenic mRNAs can ultimately increase the possibility of tumor occurrence. Given that CRD-BP is only expressed in adult cancers but not in normal tissues, targeting the CRD-BP-mRNA interaction is a good anti-cancer strategy. To study CRD-BP-KRAS mRNA interaction and to search for inhibitors of such interaction, a safe, sensitive and high throughput-based fluorescence polarization (FP) method was developed. By using a 44 nts fluorescein-labeled KRAS RNA, a library of 217 small molecules was screenedfor their ability to inhibit CRD-BP-KRAS RNA interaction. Finally, candidate small molecule inhibitors as well as effective antisense oligonucleotides (AONs) against KRAS RNA were assessed for their ability to suppress KRAS gene expression in cancer cells.