Targeting the HuR oncogenic role with a new class of inhibitors of HuR dimerization

Comprehensive meta-analysis and target screening confirmed that the mRNA-binding protein of ELAV-family HuR is oncogenic and universally upregulated in brain tumors, which highlight HuR as an universal chemotherapeutic target. HuR functionality in cancer cells is strictly dependent on HuR nuclear/cytoplasmic shuttling and dimerization; therefore, we developed a new class of inhibitors of HuR protein dimerization by utilizing medicinal chemistry techniques and reporter cell-based assay of HuR dimerization. The therapeutic potentials of lead compound (SRI-42127) were evaluated in five primary patient-derived glioma xenolines of classic, proneural, and mesenchymal subtypes, in vitro, and in mouse glioma model, in vivo. The Illumina global RNA-Sequencing was performed on PDGx-derived glioma neurospheres of different subtypes after treatment with DMSO (control) or SRI-42127 (3 uM) for 12 h to analysis transcripts and cell-signaling pathways affected by new inhibitor of HuR dimerization. Two biological replicates were analyzed for each of five PDGx cell lines in two different conditions: i) afte treatment with inhibitor of HuR dimerization SRI-42127, 3 uM for 12 hours; ii) after treatment with corresponding DMSO concentration for 12 hours.