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
  • 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.
Products