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

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 0002-7863 (

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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.


Dalton, Samuel E. ORCID logoORCID:, 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;