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.
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