Abstract
Modulation of protein–RNA interaction (PRI) using small molecules is a promising strategy to develop therapeutics. LIN28 is an RNA-binding protein that blocks the maturation of the tumor suppressor let-7 microRNAs. Herein, we performed a fluorescence polarization-based screening and identified trisubstituted pyrrolinones as small-molecule inhibitors disrupting the LIN28–let-7 interaction. The most potent compound C902 showed dose-dependent inhibition in an EMSA validation assay, enhanced thermal stability of the cold shock domain of LIN28, and increased mature let-7 levels in JAR cells. The structure–activity relationship study revealed key structural features contributing to either PRI inhibition or stabilization of protein–protein interaction (PPI). The pyrrolinones identified in this study not only represent a new class of LIN28-binding molecules that diversify the limited available LIN28 inhibitors but also represent the first examples of small molecules that showed substituent-dependent PRI inhibitory and PPI activating activities.
Highlights
Using small molecules is a promising strategy to develop therapeutics
The pyrrolinones identified in this study represent a new class of LIN28-binding molecules that diversify the limited available LIN28 inhibitors and represent the first examples of small molecules that showed substituentdependent protein−RNA interaction (PRI) inhibitory and protein− protein interaction (PPI) activating activities
Small molecules targeting protein−RNA interaction (PRI) hold great potential to be therapeutic candidates or biological probes given the diverse cellular events regulated by the interaction between RNA and RNA-binding proteins (RBPs).[1]
Summary
Using small molecules is a promising strategy to develop therapeutics. LIN28 is an RNA-binding protein that blocks the maturation of the tumor suppressor let-7 microRNAs. The pyrrolinones identified in this study represent a new class of LIN28-binding molecules that diversify the limited available LIN28 inhibitors and represent the first examples of small molecules that showed substituentdependent PRI inhibitory and PPI activating activities.
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