Selectively targeting the kinome-conserved lysine of PI3K (delta) as a general approach to covalent kinase inhibition

Sébastien André Campos, John Murphy, Samuel Dalton, Lars Dittus, Daniel Thomas, Maire Convery, Joao Nunes, Jacob Bush, John Evans, Thilo Werner, Marcus Bantscheff

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Selective covalent inhibition of kinases by targeting poorly conserved cysteines has proven highly fruitful to date in the development of chemical probes and approved drugs. However, this approach is limited to ~200 kinases possessing such a cysteine near the ATP-binding pocket. Herein, we report a novel approach to achieve selective, irreversible kinase inhibition, by targeting the conserved catalytic lysine residue. We have illustrated our approach by developing selective, covalent PI3Kδ inhibitors that exhibit nanomolar potency in cellular assays, and a duration of action >48 h in CD4+ T cells. Despite conservation of the lysine residue throughout the kinome, the lead compound shows high levels of selectivity over a selection of lipid and protein kinases in biochemical assays, as well as covalent binding to very few off-target proteins in live-cell proteomic studies. We anticipate this approach could offer an alternative general strategy, to targeting non-conserved cysteines, for the development of selective covalent kinase inhibitors.
LanguageEnglish
Number of pages8
JournalJournal of the American Chemical Society
Early online date12 Dec 2017
DOIs
Publication statusE-pub ahead of print - 12 Dec 2017

Fingerprint

Phosphatidylinositol 3-Kinases
Lysine
Assays
Phosphotransferases
Lead compounds
Proteins
Cysteine
T-cells
Adenosinetriphosphate
Lipids
Conservation
Proteomics
Protein Kinases
Adenosine Triphosphate
T-Lymphocytes
Pharmaceutical Preparations

Keywords

  • lysine
  • kinase inhibitor
  • catalytic lysine

Cite this

Campos, Sébastien André ; Murphy, John ; Dalton, Samuel ; Dittus, Lars ; Thomas, Daniel ; Convery, Maire ; Nunes, Joao ; Bush, Jacob ; Evans, John ; Werner, Thilo ; Bantscheff, Marcus. / Selectively targeting the kinome-conserved lysine of PI3K (delta) as a general approach to covalent kinase inhibition. In: Journal of the American Chemical Society. 2017.
@article{13576d4184a04789bc91dde235354d32,
title = "Selectively targeting the kinome-conserved lysine of PI3K (delta) as a general approach to covalent kinase inhibition",
abstract = "Selective covalent inhibition of kinases by targeting poorly conserved cysteines has proven highly fruitful to date in the development of chemical probes and approved drugs. However, this approach is limited to ~200 kinases possessing such a cysteine near the ATP-binding pocket. Herein, we report a novel approach to achieve selective, irreversible kinase inhibition, by targeting the conserved catalytic lysine residue. We have illustrated our approach by developing selective, covalent PI3Kδ inhibitors that exhibit nanomolar potency in cellular assays, and a duration of action >48 h in CD4+ T cells. Despite conservation of the lysine residue throughout the kinome, the lead compound shows high levels of selectivity over a selection of lipid and protein kinases in biochemical assays, as well as covalent binding to very few off-target proteins in live-cell proteomic studies. We anticipate this approach could offer an alternative general strategy, to targeting non-conserved cysteines, for the development of selective covalent kinase inhibitors.",
keywords = "lysine, kinase inhibitor, catalytic lysine",
author = "Campos, {S{\'e}bastien Andr{\'e}} and John Murphy and Samuel Dalton and Lars Dittus and Daniel Thomas and Maire Convery and Joao Nunes and Jacob Bush and John Evans and Thilo Werner and Marcus Bantscheff",
note = "This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society, copyright {\circledC} American Chemical Society after peer review. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see http://pubs.acs.org/doi/10.1021/jacs.7b08979",
year = "2017",
month = "12",
day = "12",
doi = "10.1021/jacs.7b08979",
language = "English",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",

}

Selectively targeting the kinome-conserved lysine of PI3K (delta) as a general approach to covalent kinase inhibition. / Campos, Sébastien André; Murphy, John; Dalton, Samuel; Dittus, Lars ; Thomas, Daniel; Convery, Maire; Nunes, Joao; Bush, Jacob; Evans, John; Werner, Thilo; Bantscheff, Marcus.

In: Journal of the American Chemical Society, 12.12.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Selectively targeting the kinome-conserved lysine of PI3K (delta) as a general approach to covalent kinase inhibition

AU - Campos, Sébastien André

AU - Murphy, John

AU - Dalton, Samuel

AU - Dittus, Lars

AU - Thomas, Daniel

AU - Convery, Maire

AU - Nunes, Joao

AU - Bush, Jacob

AU - Evans, John

AU - Werner, Thilo

AU - Bantscheff, Marcus

N1 - This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society, copyright © American Chemical Society after peer review. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see http://pubs.acs.org/doi/10.1021/jacs.7b08979

PY - 2017/12/12

Y1 - 2017/12/12

N2 - Selective covalent inhibition of kinases by targeting poorly conserved cysteines has proven highly fruitful to date in the development of chemical probes and approved drugs. However, this approach is limited to ~200 kinases possessing such a cysteine near the ATP-binding pocket. Herein, we report a novel approach to achieve selective, irreversible kinase inhibition, by targeting the conserved catalytic lysine residue. We have illustrated our approach by developing selective, covalent PI3Kδ inhibitors that exhibit nanomolar potency in cellular assays, and a duration of action >48 h in CD4+ T cells. Despite conservation of the lysine residue throughout the kinome, the lead compound shows high levels of selectivity over a selection of lipid and protein kinases in biochemical assays, as well as covalent binding to very few off-target proteins in live-cell proteomic studies. We anticipate this approach could offer an alternative general strategy, to targeting non-conserved cysteines, for the development of selective covalent kinase inhibitors.

AB - Selective covalent inhibition of kinases by targeting poorly conserved cysteines has proven highly fruitful to date in the development of chemical probes and approved drugs. However, this approach is limited to ~200 kinases possessing such a cysteine near the ATP-binding pocket. Herein, we report a novel approach to achieve selective, irreversible kinase inhibition, by targeting the conserved catalytic lysine residue. We have illustrated our approach by developing selective, covalent PI3Kδ inhibitors that exhibit nanomolar potency in cellular assays, and a duration of action >48 h in CD4+ T cells. Despite conservation of the lysine residue throughout the kinome, the lead compound shows high levels of selectivity over a selection of lipid and protein kinases in biochemical assays, as well as covalent binding to very few off-target proteins in live-cell proteomic studies. We anticipate this approach could offer an alternative general strategy, to targeting non-conserved cysteines, for the development of selective covalent kinase inhibitors.

KW - lysine

KW - kinase inhibitor

KW - catalytic lysine

UR - http://pubs.acs.org/doi/10.1021/jacs.7b08979

U2 - 10.1021/jacs.7b08979

DO - 10.1021/jacs.7b08979

M3 - Article

JO - Journal of the American Chemical Society

T2 - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

ER -