Discovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking

J Am Chem Soc. 2020 Mar 18;142(11):4960-4964. doi: 10.1021/jacs.9b10377. Epub 2020 Mar 4.

Abstract

Eukaryotic translation initiation factor 4E (eIF4E) binds the m7GTP cap structure at the 5'-end of mRNAs, stimulating the translation of proteins implicated in cancer cell growth and metastasis. eIF4E is a notoriously challenging target, and most of the reported inhibitors are negatively charged guanine analogues with negligible cell permeability. To overcome these challenges, we envisioned a covalent targeting strategy. As there are no cysteines near the eIF4E cap binding site, we developed a covalent docking approach focused on lysine. Taking advantage of a "make-on-demand" virtual library, we used covalent docking to identify arylsulfonyl fluorides that target a noncatalytic lysine (Lys162) in eIF4E. Guided by cocrystal structures, we elaborated arylsulfonyl fluoride 2 to 12, which to our knowledge is the first covalent eIF4E inhibitor with cellular activity. In addition to providing a new tool for acutely inactivating eIF4E in cells, our computational approach may offer a general strategy for developing selective lysine-targeted covalent ligands.

Publication types

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

MeSH terms

  • Binding Sites
  • Drug Discovery
  • Eukaryotic Initiation Factor-4E / antagonists & inhibitors*
  • Eukaryotic Initiation Factor-4E / chemistry
  • Eukaryotic Initiation Factor-4E / metabolism
  • HEK293 Cells
  • Humans
  • Lysine / chemistry*
  • Molecular Docking Simulation
  • Protein Binding
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology*

Substances

  • EIF4E protein, human
  • Eukaryotic Initiation Factor-4E
  • Sulfonamides
  • Lysine