Covalent targeting of non-cysteine residues in PI4KIIIβ

Brett Cosgrove, Emma K. Grant, Sophie Bertrand, Kenneth D. Down, Don O. Somers, John P. Evans, Nicholas C. O. Tomkinson, Michael D. Barker

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The synthesis and characterisation of fluorosulfate covalent inhibitors of the lipid kinase PI4KIIIβ is described. The conserved lysine residue located within the ATP binding site was targeted, and optimised compounds based upon reversible inhibitors with good activity and physicochemical profile showed strong reversible interactions and slow onset times for the covalent inhibition, resulting in an excellent selectivity profile for the lipid kinase target. X-Ray crystallography demonstrated a distal tyrosine residue could also be targeted using a fluorosulfate strategy. Combination of this knowledge showed that a dual covalent inhibitor could be developed which reveals potential in addressing the challenges associated with drug resistant mutations.
Original languageEnglish
Pages (from-to)1111-1122
Number of pages12
JournalRSC Chemical Biology
Issue number12
Early online date17 Oct 2023
Publication statusE-pub ahead of print - 17 Oct 2023


  • fluorosulfate covalent inhibitors
  • PI4KIIIβ
  • drug resistant mutations


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