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dc.contributor.authorSolano-Gonzalez, E.
dc.contributor.authorCoburn, K.M.
dc.contributor.authorYu, W.
dc.contributor.authorWilson, G.M.
dc.contributor.authorNurmemmedov, E.
dc.contributor.authorKesari, S.
dc.contributor.authorChang, E.T.
dc.contributor.authorMacKerell, A.D.
dc.contributor.authorWeber, D.J.
dc.contributor.authorCarrier, F.
dc.date.accessioned2021-04-12T16:48:46Z
dc.date.available2021-04-12T16:48:46Z
dc.date.issued2021-01-04
dc.identifier.urihttp://hdl.handle.net/10713/15222
dc.description.abstractWe have identified chemical probes that simultaneously inhibit cancer cell progression and an immune checkpoint. Using the computational Site Identification by Ligand Competitive Saturation (SILCS) technology, structural biology and cell-based assays, we identify small molecules that directly and selectively bind to the RNA Recognition Motif (RRM) of hnRNP A18, a regulator of protein translation in cancer cells. hnRNP A18 recognizes a specific RNA signature motif in the 3'UTR of transcripts associated with cancer cell progression (Trx, VEGF, RPA) and, as shown here, a tumor immune checkpoint (CTLA-4). Post-transcriptional regulation of immune checkpoints is a potential therapeutic strategy that remains to be exploited. The probes target hnRNP A18 RRM in vitro and in cells as evaluated by cellular target engagement. As single agents, the probes specifically disrupt hnRNP A18-RNA interactions, downregulate Trx and CTLA-4 protein levels and inhibit proliferation of several cancer cell lines without affecting the viability of normal epithelial cells. These first-in-class chemical probes will greatly facilitate the elucidation of the underexplored biological function of RNA Binding Proteins (RBPs) in cancer cells, including their effects on proliferation and immune checkpoint activation. Copyright The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.en_US
dc.description.urihttps://doi.org/10.1093/nar/gkaa1254en_US
dc.language.isoen_USen_US
dc.publisherOxford University Pressen_US
dc.relation.ispartofNucleic acids research
dc.subjectcancer cellsen_US
dc.subjectchemical probesen_US
dc.subjectprotein translationen_US
dc.subject.meshRNA-Binding Proteinsen_US
dc.titleSmall molecules inhibitors of the heterogeneous ribonuclear protein A18 (hnRNP A18): a regulator of protein translation and an immune checkpointen_US
dc.typeArticleen_US
dc.identifier.doi10.1093/nar/gkaa1254
dc.identifier.pmid33398344


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