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

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Dalton, Samuel E. and Dittus, Lars and Thomas, Daniel A. and Convery, Máire A. and Nunes, Joao and Bush, Jacob T. and Evans, John P. and Werner, Thilo and Bantscheff, Marcus and Murphy, John A. and Campos, Sebastien (2018) Selectively targeting the kinome-conserved lysine of PI3K (delta) as a general approach to covalent kinase inhibition. Journal of the American Chemical Society, 140 (3). pp. 932-939. ISSN 1520-5126 (https://doi.org/10.1021/jacs.7b08979)

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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.

ORCID iDs

Dalton, Samuel E. ORCID logoORCID: https://orcid.org/0000-0001-7806-247X, Dittus, Lars, Thomas, Daniel A., Convery, Máire A., Nunes, Joao, Bush, Jacob T., Evans, John P., Werner, Thilo, Bantscheff, Marcus, Murphy, John A. and Campos, Sebastien;
  • Item type:Article
    ID code:62960
    Dates:
    Date
    Event
    24 January 2018
    Published
    12 December 2017
    Published Online
    22 August 2017
    Accepted
    Notes: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
    Subjects:Science > Chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:22 Jan 2018 09:49
    Last modified:12 Dec 2024 06:09
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/62960
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