Issue 12, 2023

Covalent targeting of non-cysteine residues in PI4KIIIβ

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.

Graphical abstract: Covalent targeting of non-cysteine residues in PI4KIIIβ

Supplementary files

Article information

Article type
Paper
Submitted
31 Jul 2023
Accepted
11 Oct 2023
First published
17 Oct 2023
This article is Open Access
Creative Commons BY license

RSC Chem. Biol., 2023,4, 1111-1122

Covalent targeting of non-cysteine residues in PI4KIIIβ

B. Cosgrove, E. K. Grant, S. Bertrand, K. D. Down, D. O. Somers, J. P. Evans, N. C. O. Tomkinson and M. D. Barker, RSC Chem. Biol., 2023, 4, 1111 DOI: 10.1039/D3CB00142C

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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