Reversible Lysine-targeted Probes Reveal Residence Time-based Kinase Selectivity

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2022 May 19

PMID 35590003

Authors

Tangpo Yang

Adolfo Cuesta

Xiaobo Wan

Gregory B Craven

Brad Hirakawa

Penney Khamphavong

Jeffrey R May

John C Kath

John D Lapek Jr

Sherry Niessen

Alma L Burlingame

Jordan D Carelli

Jack Taunton

Affiliations

Soon will be listed here.

Abstract

The expansion of the target landscape of covalent inhibitors requires the engagement of nucleophiles beyond cysteine. Although the conserved catalytic lysine in protein kinases is an attractive candidate for a covalent approach, selectivity remains an obvious challenge. Moreover, few covalent inhibitors have been shown to engage the kinase catalytic lysine in animals. We hypothesized that reversible, lysine-targeted inhibitors could provide sustained kinase engagement in vivo, with selectivity driven in part by differences in residence time. By strategically linking benzaldehydes to a promiscuous kinase binding scaffold, we developed chemoproteomic probes that reversibly and covalently engage >200 protein kinases in cells and mice. Probe-kinase residence time was dramatically enhanced by a hydroxyl group ortho to the aldehyde. Remarkably, only a few kinases, including Aurora A, showed sustained, quasi-irreversible occupancy in vivo, the structural basis for which was revealed by X-ray crystallography. We anticipate broad application of salicylaldehyde-based probes to proteins that lack a druggable cysteine.

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