2. Academic Validation
  3. Small-Molecule Inhibitors Disrupt let-7 Oligouridylation and Release the Selective Blockade of let-7 Processing by LIN28

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.
Longfei Wang 1,  R Grant Rowe 2,  Adriana Jaimes 1,  Chunxiao Yu 1,  Yunsun Nam 1,  Daniel S Pearson 3,  Jin Zhang 3,  Xiangyu Xie 1,  William Marion 3,  Gregory J Heffron 1,  George Q Daley 4,  Piotr Sliz 5
Affiliations

Affiliations

  • 1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 2 Stem Cell Program, Boston Children's Hospital, Boston, MA, USA; Department of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA, USA.
  • 3 Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.
  • 4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Stem Cell Program, Boston Children's Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA; Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA; Manton Center for Orphan Disease Research, Boston, MA, USA.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA. Electronic address: [email protected].
PMID: 29874593 DOI: 10.1016/j.celrep.2018.04.116
Abstract

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.

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