Small-Molecule Inhibitors Disrupt let-7 Oligouridylation and Release the Selective Blockade of let-7 Processing by LIN28

Cell Rep. 2018 Jun 5;23(10):3091-3101. doi: 10.1016/j.celrep.2018.04.116.


LIN28 is an RNA-binding protein that regulates the maturation of the let-7 family of microRNAs by bipartite interactions with let-7 precursors through its two distinct cold shock and zinc-knuckle domains. Through inhibition of let-7 biogenesis, LIN28 functions as a pluripotency factor, as well as a driver of tumorigenesis. Here, we report a fluorescence polarization assay to identify small-molecule inhibitors for both domains of LIN28 involved in let-7 interactions. Of 101,017 compounds screened, six inhibit LIN28:let-7 binding and impair LIN28-mediated let-7 oligouridylation. Upon further characterization, we demonstrate that the LIN28 inhibitor TPEN destabilizes the zinc-knuckle domain of LIN28, while LI71 binds the cold shock domain to suppress LIN28's activity against let-7 in leukemia cells and embryonic stem cells. Our results demonstrate selective pharmacologic inhibition of individual domains of LIN28 and provide a foundation for therapeutic inhibition of the let-7 biogenesis pathway in LIN28-driven diseases.

Keywords: 5-(methylamino)nicotinic acid; LI71; LIN28; LIN28 inhibitor; TPEN; TUT4; TUTase; let-7; oligouridylation; pre-let-7.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line, Tumor
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / metabolism
  • Fluorescence Polarization
  • High-Throughput Screening Assays
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Models, Molecular
  • Niacin / chemistry
  • RNA Processing, Post-Transcriptional*
  • RNA-Binding Proteins / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Uridine / metabolism*


  • Lin28A protein, human
  • MicroRNAs
  • RNA-Binding Proteins
  • Small Molecule Libraries
  • mirnlet7 microRNA, human
  • Niacin
  • Uridine