TY - JOUR T1 - Small molecule inhibition of multiple RNA binding proteins underlies Musashi-2 independent phenotypes JF - bioRxiv DO - 10.1101/2022.09.20.508735 SP - 2022.09.20.508735 AU - Kathryn Walters AU - Marcin Piotr Sajek AU - Aaron Issaian AU - Amber Baldwin AU - Evan Harrison AU - Elisabeth Murphy AU - Miles Daniels AU - Julie Haines AU - Kirk Hansen AU - Angelo D’Alessandro AU - Neelanjan Mukherjee Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/09/20/2022.09.20.508735.abstract N2 - 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 inhibitor identified as a competitive inhibitor of Musashi(MSI)-RNA interactions. Here we show Ro potently inhibits adrenocortical steroidogenesis and viability independent of MSI2 in multiple cell lines. We identified Ro-interacting proteins using an unbiased proteome-wide approach and discovered it is broadly targeting RBPs. To confirm this finding, we leveraged the large-scale ENCODE data and found a subset of RBPs whose depletion phenocopies Ro inhibition. We conclude that Ro is a promiscuous inhibitor of multiple RBPs, many containing RRM1 domains. Moreover, we provide a general framework for validating the specificity and identifying targets of RBP inhibitors in a cellular context.Competing Interest StatementThe authors have declared no competing interest. ER -