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

Longfei Wang, R. Grant Rowe, Adriana Jaimes, Chunxiao Yu, Yunsun Nam, Daniel S. Pearson, Jin Zhang, Xiangyu Xie, William Marion, Gregory J. Heffron, George Q. Daley, Piotr Sliz

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


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. LIN28 is an oncogenic protein that promotes transformation in malignancy by suppressing the maturation of let-7 microRNAs. Wang et al. developed a high-throughput screening strategy and identified inhibitors of LIN28 that restore mature let-7 levels.

Original languageEnglish (US)
Pages (from-to)3091-3101
Number of pages11
JournalCell Reports
Issue number10
StatePublished - Jun 5 2018


  • 5-(methylamino)nicotinic acid
  • LI71
  • LIN28
  • LIN28 inhibitor
  • TPEN
  • TUT4
  • TUTase
  • let-7
  • oligouridylation
  • pre-let-7

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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