Open AccessDiscovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking
Author(s) -
Xiaobo Wan,
Tangpo Yang,
Adolfo Cuesta,
Xiaming Pang,
Trent E. Balius,
John J. Irwin,
Brian K. Shoichet,
Jack Taunton
Publication year - 2020
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.9b10377
Subject(s) - chemistry , covalent bond , eif4e , lysine , docking (animal) , eukaryotic translation , biochemistry , computational biology , translation (biology) , amino acid , biology , messenger rna , medicine , nursing , organic chemistry , gene
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.