Covalent targeting of non-cysteine residues in PI4KIIIβ

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Cosgrove, Brett and Grant, Emma K. and Bertrand, Sophie and Down, Kenneth D. and Somers, Don O. and P. Evans, John and Tomkinson, Nicholas C. O. and Barker, Michael D. (2023) Covalent targeting of non-cysteine residues in PI4KIIIβ. RSC Chemical Biology, 4 (12). pp. 1111-1122. ISSN 2633-0679 (https://doi.org/10.1039/d3cb00142c)

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Abstract

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.

ORCID iDs

Cosgrove, Brett, Grant, Emma K., Bertrand, Sophie, Down, Kenneth D., Somers, Don O., P. Evans, John, Tomkinson, Nicholas C. O. ORCID logoORCID: https://orcid.org/0000-0002-5509-0133 and Barker, Michael D.;
  • Item type:Article
    ID code:86998
    Dates:
    Date
    Event
    17 October 2023
    Published
    17 October 2023
    Published Online
    11 October 2023
    Accepted
    31 July 2023
    Submitted
    Subjects:Science > Natural history > Biology
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:19 Oct 2023 08:40
    Last modified:16 Dec 2024 02:46
    URI:https://strathprints.strath.ac.uk/id/eprint/86998
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