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Small molecule inhibition of multiple RNA binding proteins by Ro-08-2750 underlies Musashi-2 independent phenotypes.

Kathryn WaltersMarcin Piotr SajekElisabeth MurphyAaron IssaianAmber BaldwinEvan HarrisonMiles DanielsJulie HainesKirk C HansenAngelo D'AlessandroNeelanjan Mukherjee
Published in: RNA (New York, N.Y.) (2023)
RNA binding proteins (RBPs) are key regulators of gene expression. Small molecules targeting these RBP-RNA interactions are a rapidly emerging class of therapeutics for treating a variety of diseases. Ro-08-2750 (Ro) is a small molecule identified as a competitive inhibitor of Musashi (MSI)-RNA interactions. Here we show multiple Ro-dependent cellular phenotypes, specifically adrenocortical steroid production and cell viability, are MSI2 independent. Using an unbiased proteome-wide approach we discovered Ro broadly interacts with RBPs, many containing RRM domains. To confirm this finding, we leveraged the large-scale ENCODE data to identify a subset of RBPs whose depletion phenocopies Ro inhibition, indicating Ro is a promiscuous inhibitor of multiple RBPs. Consistent with broad disruption of ribonucleoprotein complexes, Ro treatment leads to stress granule formation. This strategy represents a generalizable framework for validating the specificity and identifying targets of RBP inhibitors in a cellular context.
Keyphrases
  • small molecule
  • gene expression
  • dna methylation
  • protein protein
  • nucleic acid
  • transcription factor
  • drug delivery
  • machine learning
  • electronic health record
  • artificial intelligence