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

doi:10.1039/d3cb00142c

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^*

^*Corresponding author for this work

Pure And Applied Chemistry

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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.

Original language	English
Pages (from-to)	1111-1122
Number of pages	12
Journal	RSC Chemical Biology
Volume	4
Issue number	12
Early online date	17 Oct 2023
DOIs	https://doi.org/10.1039/d3cb00142c
Publication status	E-pub ahead of print - 17 Oct 2023

Keywords

fluorosulfate covalent inhibitors
PI4KIIIβ
drug resistant mutations

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10.1039/d3cb00142cLicence: CC BY 3.0

Cosgrove-etal-RSCCB-2023-Covalent-targeting-of-non-cysteine-residues-in-PI4KIIIβFinal published version, 2.14 MBLicence: CC BY 3.0

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title = "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.",

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author = "Brett Cosgrove and Grant, {Emma K.} and Sophie Bertrand and Down, {Kenneth D.} and Somers, {Don O.} and {P. Evans}, John and Tomkinson, {Nicholas C. O.} and Barker, {Michael D.}",

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doi = "10.1039/d3cb00142c",

language = "English",

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T1 - Covalent targeting of non-cysteine residues in PI4KIIIβ

AU - Cosgrove, Brett

AU - Grant, Emma K.

AU - Bertrand, Sophie

AU - Down, Kenneth D.

AU - Somers, Don O.

AU - P. Evans, John

AU - Tomkinson, Nicholas C. O.

AU - Barker, Michael D.

PY - 2023/10/17

Y1 - 2023/10/17

N2 - 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.

AB - 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.

KW - fluorosulfate covalent inhibitors

KW - PI4KIIIβ

KW - drug resistant mutations

U2 - 10.1039/d3cb00142c

DO - 10.1039/d3cb00142c

M3 - Article

VL - 4

SP - 1111

EP - 1122

JO - RSC Chemical Biology

JF - RSC Chemical Biology

IS - 12

ER -

Covalent targeting of non-cysteine residues in PI4KIIIβ

Abstract

Keywords

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